Next Article in Journal
The Influence of the Auxiliary Ligand in Monofunctional Pt(II) Anticancer Complexes on the DNA Backbone
Previous Article in Journal
Human Brain In Vitro Model for Pathogen Infection-Related Neurodegeneration Study
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

by
Francisco Revert-Ros
,
Ignacio Ventura
,
Jesús A. Prieto-Ruiz
,
José Miguel Hernández-Andreu
and
Fernando Revert
*
Mitochondrial and Molecular Medicine Research Group, Facultad de Medicina y Ciencias de la Salud, Universidad Católica de Valencia San Vicente Mártir, 46001 Valencia, Spain
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2024, 25(12), 6523; https://doi.org/10.3390/ijms25126523
Submission received: 8 May 2024 / Revised: 1 June 2024 / Accepted: 8 June 2024 / Published: 13 June 2024
(This article belongs to the Special Issue Targeting Collagen-Related Therapy)

Abstract

:
Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.

1. Introduction

Human collagens are oligomeric proteins that encompass a family of 28 members, 44 genes, and 1 pseudogene with 2 variants ([1] and Table 1). The basic molecular units, or protomers, of collagen consist of three twisted α chains, i.e., a triple-helical polypeptide. The steric restriction of the triple helix requires a primary structure with collagenous domains, repetitions of Gly-X-Y motifs, with X and Y frequently being proline and 4-hydroxyproline, which also stabilize the quaternary structure. In collagens I, II, III, and V/XI, 3-hydroxyproline has also been identified. The protomers are normally homotrimers, in which the three polypeptides are the same since most of the collagens have just one type of polypeptide. However, there are 7 types of collagen with more than one α chain (I, IV, V, VI, VIII, IX, XI). Among these, homotrimers have been observed only in collagen VIII, while the rest are heterotrimers of polypeptides of the same family. Just two mixed-heterotrimeric protomers have been described: α1(II)-α1(XI)-α2(XI) and α1(II)-α1(V)-α1(XI). Although the number of potential heterotrimeric combinations is very high, the number of characterized heterotrimers is quite limited ([1] and Table 1). Enclosed, please find a comprehensive list of collagen genes in the OMIM database (Table S1).
The utilization of two alternative promoters in the COL9A1 and COL18A1 genes results in the production of distinct forms of the encoded chains [2,3]. Additionally, alternative splicing contributes to the presence of multiple isoforms in 10 collagen genes (Table 1). The process of alternative splicing is recognized for exhibiting tissue- or development-specific patterns, as exemplified by COL2A1 [4]. However, in various instances, the functional consequences remain elusive. Notably, various types of collagens, such as IX (which binds to collagen II), XII, XIV, XV, and XVIII, are known to harbor glycosaminoglycan chains. These chains include chondroitin sulfate, dermatan sulfate, and heparan sulfate, which can be present in diverse combinations. This characteristic classifies them as proteoglycans [5,6,7,8,9].
The definition of collagen is blurry since there are a variety of quaternary structures, cellular and tissue localizations, and functions that are not necessarily related. Several molecules with collagen-like domains have not been classified as collagens. These molecules could be extracellular matrix components (e.g., emilins) playing a structural role [10]; however, in other cases, the collagen-like trimeric structure is part of the molecule that tightens its interactive and functional domains (e.g., adiponectin or complement 1q) [11].
The extracellular functions of collagen could be understood from a phylogenetic point of view. Collagen IV is the first ancestor in the phylogenetic tree, and it is directly associated with the transition to multicellularity by enabling the genesis of multicellular epithelial tissues [12]. It is noteworthy that some ancestors of collagen IV did not associate with epithelial differentiation [12,13]; in this sense, human collagen IV displays structural diversification [14,15,16], which could be associated with mesenchymal microenvironments [15]. The subsequent position on the phylogenetic tree of fibrillar collagens (collagen I) correlates with the structure of the mesenchyme and the connective tissues derived from it ([12] and Figure 1).
When viewed collectively as a family, the expression and distribution of collagen span a wide range. However, upon closer examination of each type of collagen individually, it becomes apparent that their biological functions are primarily tissue- or organ-specific. This observation is supported by the variety of diseases caused by pathological mutations identified to date, as outlined in Table 1 and Table S1.

2. Collagen-Related Diseases

Targeting collagen becomes logical when the focus is on diseases marked by excessive collagen production or where collagen plays a pivotal role in exacerbating pathological processes. On the other hand, a mutation in collagen genes could be the cause of a disease (Table 1 and Table S1). In this case, the expression of recombinant or genome-edited collagens in the affected tissue could be an option. While the following section is not comprehensive, it offers a brief overview of the role of collagens in several pathophysiological conditions, focusing on diseases treated in the following sections.

2.1. Fibrosis and Wound Healing

Fibrosis is a pathological process characterized by the excessive accumulation of scar or fibrous tissue. Fibrotic tissue primarily consists of types I and III collagens, along with a combination of fibrotic cells [17]. Tissues displaying an excess of fibrosis often encounter prolonged healing challenges, potentially resulting in dysfunction of organs or tissues. It is also a pathogenic factor in cancer (see below) [18].
Fibrosis may occur either primarily, with no identifiable cause (idiopathic) or as a secondary response to a range of factors. These factors include chronic infections or inflammation, autoimmune diseases, exposure to toxins, radiation, or chemical compounds, as well as conditions like atherosclerosis, venous insufficiency, and cancer [17,19].
Depending on the organ affected by fibrosis, a number of diseases have been described. Idiopathic pulmonary fibrosis has been associated with alterations in the deposition of type I and type III collagen, which contribute to pulmonary interstitial remodeling and respiratory dysfunction [20]. Exposure to chemicals such as asbestos, cigarette smoke, drugs, or radiation or pathogens, can lead to secondary pulmonary fibrosis [21]. Other primary fibrotic phenomena include Dupuytren’s contracture, a chronic connective disorder of the palmar fascia of the hand, resulting in a progressive contracture in flexion of the finger [22]; and Peyronie’s disease, a condition in which men develop plaques of fibrous tissue in their penis, leading to pain or difficulty in sexual intercourse [23].
Liver fibrosis is normally secondary to chronic damage (alcohol, viruses, etc.). An increase in collagen type I deposition starting in the portal triads leads to fibrogenesis and the progression of hepatic cirrhosis. Stellate cells situated within the hepatic sinusoids play a pivotal role in the advancement of liver fibrosis [24]. A similar condition is found in the pancreas, where pancreatic stellate cells mediate fibrosis, potentially leading to chronic pancreatitis and cancer [25]. Cardiac fibrosis can also be secondary to various phenomena, resulting in distinct histological patterns. Ischemic cardiomyopathy, for instance, prompts interstitial fibrosis, which replaces the original muscle tissue. In contrast, dilated cardiomyopathy, which could be the end stage of hypertensive heart disease, induces diffuse fibrosis throughout the muscle tissue [26]. Although type I collagen traditionally takes center stage in these processes, recent findings have revealed that type IV collagen, along with other collagens, also significantly contributes to the scarring process in necrotic cardiac muscle [27].
Systemic sclerosis, also known as scleroderma, is a fibrotic condition that impacts various organs due to an autoimmune process. This chronic disease, whose etiology remains unknown, is typified by extensive fibrosis and vascular aberrancies occurring throughout the skin, joints, and internal organs, notably the esophagus, lower gastrointestinal tract, lungs, heart, and kidneys. Scleroderma (skin thickening) is indeed the expression of systemic sclerosis in the skin. In skin biopsy, atrophic areas are evident, showing increased collagen deposition and a reduction in the spaces between normal collagen bundles [28]. Keloids result from abnormal wound healing processes characterized by excessive accumulation of collagen within the scar tissue [29]. Renal sclerosis, distinct from fibrosis, is linked to alterations in the expression of type IV collagen. Changes in the deposition of collagen type IV play a role in glomerular dysfunction and the advancement of chronic kidney disease secondary to certain glomerulopathies, such as IgA nephropathy [30]. The ultimate stage would be fibrosis, marked by an early increase in the expression of collagen I and III [31].

2.2. Cancer

Network collagens and fibrillar (plus FACIT) collagens play different roles in the pathogenesis and progression of cancer. Their overexpression has been described in multiple types of cancer. However, both families of collagens interact with different integrins and discoidin domain receptors (DDRs) to initiate multiple signaling pathways that lead to cancer cell proliferation, survival, invasion, and metastasis [32,33].
The distribution of network collagens varies significantly. Epithelial cells are the main producers of collagen IV, while collagen VIII is predominantly located in corneal and vascular endothelial tissues, and collagen VI and X are typically found in connective tissues, where they are associated with fibrillar collagens. Therefore, tumors originating from epithelial cells are primarily associated with collagen IV expression in their pathogenesis. The progression of these tumors could be correlated with a shift in the type of collagen IV being secreted, which provides survival signals to cancerous cells that have acquired mesenchymal properties [15].
A relatively high expression of fibrillar collagen is associated with an unfavorable prognosis in many types of tumors, which is especially evident in papillary and clear-cell kidney cancers and bladder cancer. Fibrillar collagens also interact with integrins and DDRs to regulate the immune response [33]. Interestingly, while an excess of collagen I is considered pro-tumoral [34], the expression of collagen III is associated with a reduction of metastasis in murine models of breast cancer [35]. Moreover, collagen III induces quiescence in cancerous cells [36]. Nevertheless, it remains a negative prognostic indicator [33].

2.3. Hemostasis

Collagen plays a crucial role in blood clotting, particularly in the formation of the initial platelet plug. When blood vessels are damaged under flow, platelets adhere to the exposed collagen via the glycoprotein GPIb. Collagen does not bind directly to the platelet receptors but through a molecular bridge called von Willebrand factor (VWF). This initial adhesion triggers a series of events leading to platelet activation and aggregation, forming a platelet plug at the site of injury. Subsequent interaction of platelets with collagen, via GPVI or integrin α2β1, and with other ECM components, improves the stability of the plug. The integrity of the vessels depends on type I, III, IV, and VI collagens. Meanwhile, multiplexing found in the basement membrane mediates the inflammatory response [37,38].
Strategies to impede the functions of collagen that contribute to disease progression can be pursued through direct or indirect approaches (Figure 2). Indirect methods involve targeting proteins essential for collagen’s structural organization or its function within the disease context. Alternatively, therapeutic interventions may involve the utilization of collagens or derived peptides to activate biochemical processes.

2.4. Genetic Disorders

Several diseases are caused by mutations in the genes encoding collagen or collagen-related proteins (Table S1). The pathophysiology encompasses extracellular (reduced matrix) as well as intracellular effects (ER stress, apoptosis) [39].
Three pathological conditions have been treated using gene therapy procedures: osteogenesis imperfecta, which results from mutations in the COL1A1 or COL1A2 genes and can manifest with bone fragility, blue sclerae, hearing loss, and dental issues [40]; epidermolysis bullosa, a consequence of mutations in COL7A1, which is characterized by a fragile skin that blisters and tears from minor friction or trauma [41]; and junctional epidermolysis bullosa, with mutations in COL17A1, and similar symptoms [41].

3. Direct Targeting

3.1. Collagenases

Numerous microorganisms secrete enzymes that break down collagen, facilitating the invasion of human tissues. The corresponding recombinant enzymes could be employed to digest collagen in vivo. One notable example is the collagenase from Clostridium histolyticum (CCH), which is effective and well tolerated in the short term in patients with Dupuytren’s contractures [42] and has been authorized for localized subcutaneous treatment. The recurrence of Dupuytren’s contracture treated with CCH is relatively low, demonstrating an efficacy similar to that of alternative treatments such as fasciectomy [43,44]. CCH is also one of the best treatments for Peyronie’s disease [45]. However, the CCH formulation known as Xiapex® (or AA4500) is presently unauthorized by the European Medicines Agency. The withdrawal was at the request of the marketing authorization holder, Swedish Orphan Biovitrum AB (publ), which notified the European Commission of its decision to permanently discontinue the marketing of the product for commercial reasons [46].
While CCH has shown relative safety and efficacy, it can trigger the production of neutralizing antibodies in patients [47]. Additionally, AA4500 has proven ineffective in treating other fibrotic conditions, such as adhesive capsulitis of the shoulder [48]. Potential future applications abound. For instance, administering a collagenase solution within the abdominal cavity reduced tumor volume in animal models [49] and could potentially enhance chemotherapy effectiveness [50].
Another approved formulation of CCH is an ointment, marketed under the brand name Santyl®, which has received FDA approval for debriding chronic dermal ulcers and severely burned areas. The enzyme releases matrix fragments (mainly non-collagen peptides) that improve healing in vivo [51]. Interestingly, collagen degradation appears to be linked to an anti-inflammatory immune response and the production of TGFβ [52].
There are several eukaryotic enzymes responsible for the turnover of collagen in the extracellular matrix. Collagenases, or matrix metalloproteinases 1, 8, 13, and 18 (MMP-1, MMP-8, MMP-13, MMP-18), and gelatinase A and B (MMP-2 and MMP-9, respectively) degrade essentially different types of collagens [53,54]. These enzymes are members of a large family of zinc-dependent extracellular matrix remodeling endopeptidases with additional substrates such as aggrecan, entactin, fibronectin, laminin, elastin, and other components of the extracellular matrix. Its enzymatic activity is regulated by natural inhibitors (tissue inhibitors of MMPs or TIMPs) [53,54]. MMPs and TIMPS are also involved in cancer and many other diseases [54]. In this case, a high or dysregulated activity had been associated with cancer progression. Moreover, several relevant pharmaceutical companies developed their own inhibitors (Table 46 from [55]), leading to a competitive race that resulted in a fiasco [56]. The first therapeutic approach was with pan-inhibitors of MMPs; however, no drug has been demonstrated to be effective for the treatment of cancer. Additionally, treatments were not well tolerated [56]. In this case, the effect on collagen is indirect. Recent efforts include specifically targeting MMP-9 with a monoclonal antibody (Andecaliximab/GS-5745), which resulted in unsatisfactory outcomes in gastric cancer [57,58], and Chron’s disease [59]. To our knowledge, MMPs have not been proposed as therapeutic agents for directly breaking down collagen in vivo.

3.2. Targeting Collagen with Biding Proteins and Peptides

Tumor collagen has been proposed as a specific target. Collagen-binding macromolecules could easily bind and accumulate in the tumor collagen. Consequently, targeting the collagen of the tumor extracellular matrix could enhance the accumulation and retention of immunotherapy drugs, thus improving their efficacy and reducing adverse effects. Collagen-binding domains (CBD) or proteins (CBP) have been proposed as candidates in tumor-targeting immunotherapy. CBD is a type of protein domain that binds specifically to collagen. CBD is derived or designed from collagen-binding sites in natural ligands of collagen, such as fibronectin (FN), VWF, placental growth factor (PlGF), and collagenase [60]. It has been reported that FN binds to types I and II collagens with high affinity [61,62]. Since FN plays an important role in wound healing and human growth, its collagen-binding domain has been mainly used to promote wound healing or treat developmental defects [63]. VWF, which mediates the adhesion of blood platelets, also promotes hemostasis by stabilizing coagulation factor VIII [64]. VWF could bind with high affinity to collagen types I, III, IV, and VI [65]. Some CBD of VWF has been used in collagen-targeting therapies for vascular repair [66], bone regeneration [60], and tumor treatment [67]. PlGF, a member of the VEGF family, participates in promoting angiogenesis, chondrogenesis, wound healing, and tumor growth [68]. Fragments of PlGF exhibit remarkably robust and indiscriminate binding to ECM components, not limited to collagen I. They have been utilized for delivering growth factors for tissue repair purposes [69]. Small collagen-binding peptides have been designed for better application with effective collagen-binding ability. Some examples are the heptapeptide TKKTLRT [70], used in regenerative medicine for efficient targeting of drugs to collagen, among other applications [71], and collagen mimetic peptides (CMP), especially interesting in diseases that present collagen degeneration [72].
In addition to collagen-binding domains, some small proteins such as lumican, bacterial surface proteins and avimers with collagen affinity are also assayed. Lumican is present in the ECM of cornea, gristle, and skin [73], and it has been shown to bind to collagenous fibers, strengthen their structure, and potentiate wound healing [74]. Lumican fused to therapeutic cytokines has been used for cancer immunotherapy, increasing the retention of drugs within tumors and reducing adverse effects [75]. Bacterial surface proteins such as lipoprotein SLR, M, and M-like proteins possess collagen affinity for infection at collagen-exposed wounds [76]. Finally, some avimers (a numerous group of small proteins that mediates the interaction between proteins) showing high collagen affinity were fused to IL-1 for the treatment of joint diseases [77].

4. Indirect Targeting

Given the intricate nature of the multiple stages associated with the development of a complex supramolecular structure, there exists considerable potential for identifying indirect targets within the process of collagen formation (Figure 2).

4.1. Translation

One of the most promising opportunities could arise at the translation level. The mammalian target of rapamycin complex 1 (mTORC1) phosphorylation of La-related protein 6 (LARP6) boosts the translation of a limited number of collagen mRNAs [78]. To date, the only described substrates of LARP6 are COL1A1, COL1A2, and COL3A1. Furthermore, LARP6 appears to be dispensable for the baseline expression of these collagens, indicating that a targeted pharmacological intervention linked to its overexpression could be achieved, potentially reducing adverse reactions. In this sense, the first tricyclic compound displaying inhibitory activity of LARP6 (C9) shows promising prophylactic and therapeutic effects in several rat models of liver fibrosis. It was isolated through an in vitro screening process involving 50,000 drug-like compounds [79]. A broader pharmacological effect can be observed with the inhibition of mTOR (part of mTORC1 and mTORC2). Along with the downregulation of collagen expression, this pathway modifies the expression of additional genes involved in epithelial-mesenchymal transition, fibrosis, inflammation, survival, autophagy, and other pathways [80]. Silibinin, a natural flavonoid, which has been described as a potential STAT3 (Signal transducer and activator of transcription 3) inhibitor with antimetastatic activity [81], has been also identified as a suppressor of the mTOR signaling pathway, reducing collagen I and III expression [82]. However, at this moment, no results from animal models have been reported.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate gene expression by binding to target mRNAs, leading to their repression or degradation. They play a role in both physiological and pathological conditions [83]. The microRNA miR-29, with three mature members, miR-29a, miR-29b, and miR-29c, has been described as a mediator of the TGF-β pathway, inhibiting the expression of various collagens (I, III, IV, or XV) and other proteins in the extracellular matrix [84,85]. It plays a relevant role in fibrosis [86]. The pharmacological potential of miR-29a has been demonstrated in a mouse model of liver fibrosis induced by CCl4. Injection of miR-29a into the vein tail improved fibrosis by inhibiting the expression of COL1A1 mRNA, among other possible mechanisms [87]. Its prophylactic and therapeutic effects in vivo have been recently confirmed using a bleomycin-induced lung fibrosis mouse model intravenously treated with a more stable mimic of miR-29 (MRG-229) [88]. MRG-229, an enhanced formulation of Remlarsen (MRG-201), has undergone testing with a limited number of patients for the prevention or reduction of keloid formation. However, intradermal injection at the site of excisional wounds yielded unsatisfactory outcomes [89].
Additional miRNAs and circular and long noncoding RNAs have been proposed as regulators of COL1A1 or COL3A1 expression. Experimentally assessed are: miR-98, miR-126- 5p, miR-218-5p, miR-328-3p, miR-338-3p [90], miR-133a and let-7 family [91]; however, none of them have been assayed as potential drugs.

4.2. Prolyl-Hydroxylation

Collagens follow the secretory pathway, and numerous enzymes and chaperones play roles in collagen formation. Hydroxylation (3- and 4-) of prolines and lysins plays a crucial role in stabilizing collagens (both fibrillar and non-fibrillar) and promotes interactions with cellular collagen receptors, such as integrins and DDRs.
Prolyl-4-hydroxylation, mediated by prolyl-4-hydroxylases (P4H), involves α2β2 heterotetramers with catalytical α-subunits (P4HA1, P4HA2, P4HA3) and the structural β-subunit protein disulfide isomerase (P4HB or PDI) [92,93]. The redox activity of P4h1 requires Fe+2 and α-ketoglutarate. Pyridine 2,5-dicarboxylate, a mimetic of α-ketoglutarate, which inhibits P4h, notably decreased collagen production in vitro and mitigated lung fibrosis while enhancing survival in a murine model induced by bleomycin [94]. Prolyl-4-hydroxylation is a modification present in essentially all types of collagens and the drug could inhibit other enzymes that use α-ketoglutarate. Additionally, the consequences of P4h activity are not restricted to collagen; they impact the overall phenotype of the cell (e.g., stemness or Warburg effect) [95]. In this case, the treatment was locally applied via an intra-tracheal spray, initiated after injury induced by bleomycin, which improves the specificity in this complex scenario [94]. Another α-ketoglutarate analog inhibitor of P4h is ethyl-3,4-dihydroxybenzoate, which impairs the production of collagen in vitro. It is also known for its antioxidant properties [96]. An intraperitoneal treatment with this compound showed anti-metastatic effects in an orthotopic breast cancer NOD/SCID mouse model. It also somewhat slowed the growth of primary tumors, although the exact mechanism is not fully understood and could involve several pharmacological targets. Using this model, researchers found that downregulating the expression of P4HA1 or P4HA2 in the cancerous cells (triple negative MDA-MB-231) with specific shRNAs greatly reduced collagen levels and significantly slowed tumor progression [96].
Prolyl-3-hydroxylation, less common, is carried out by collagen prolyl-3-hydroxylases (P3H1, P3H2, P3H3, P3H4). The prolyl-3-hydroxylases form different complexes and modify different substrates: e.g., prolyl 3-hydroxylase 1 (P3H1), cartilage-associated protein (CRTAP), and cyclophilin B (PPIB) assemble into a complex within the endoplasmic reticulum that hydroxylates proline in α1(I) and α1(II) [97]. Interestingly, cyclophilin B also regulates collagen folding and contributes to both prolyl 3-hydroxylation and lysine hydroxylation of collagen [98,99]. Recently, it has been proposed that the macrocyclic natural compound sanglifehrin A targets cyclophilin B. This interaction prompts the secretion of cyclophilin B into the extracellular space, subsequently leading to a reduction in the synthesis of type I collagen. Notably, this effect occurs without inhibiting collagen mRNA transcription or inducing endoplasmic reticulum stress. The therapeutic injection of this compound exhibits a reduction in fibrosis and immune activation in both a bleomycin-induced mouse model of skin fibrosis and lung fibrosis [100]. Other potential targets include P3h2 and P3h4. P3h2 facilitates type IV collagen prolyl-hydroxylation, a process that hinders platelet aggregation in vivo [101], while P3h4 has been identified as a prognostic factor for bladder cancer and a potential target in vivo [102]. However, no drugs targeting these proteins have been reported to date.

4.3. Lysil-Hydroxylation

Lysyl hydroxylases, including Lh1, Lh2, and Lh3 (PLOD1, PLOD2, PLOD3), hydroxylate lysines within the ER, which are linked to glycosylation. While all three LH isoforms hydroxylate the helical domain. Lh1 prefers triple-helical collagen regions, while LH2 acts on noncollagenous regions (telopeptides). Lh3 also catalyzes O-glycosylation. Each isoform possesses two functionally distinct enzymatically active domains. All of this suggests that specificity could be a hallmark of Lh2 pharmacology; however, reduced activity of Lh2 produces deleterious effects in bones and its absence impedes embryogenesis [103]. Despite that, we know that PLOD2 is upregulated and a bad prognostic factor in cancer and that Lh2 drives Epithelial-to-Mesenchymal Transition (EMT) in vitro [104]. Recently, it has been reported that Lh2-mediated extracellular matrix remodeling promotes invasiveness and metastasis in an orthotopic xenograft mice model [105]. Finally, specific inhibitors of Lh2 have been isolated and display antimigratory activity in vitro [106], although their efficacy has not yet been demonstrated in vivo.

4.4. Glycosylation

The hydroxylation of lysine residues in collagen is indeed necessary for subsequent glycosylation. Collagen glycosyltransferases, Glt25d1 and Glt25d2 (COLGALT1, COLGALT2), mediate O-glycosylation of hydroxylysines with Glc(α1-2)-Gal(β1-O) or Gal(β1-O) alone. All these processes occur prior to the assembly of the three procollagen chains. This activity plays a crucial role in the stability and function of collagen fibrils in connective tissues. In this sense, the abolition or downregulation of GLT25D1 expression leads to an accumulation of type I collagen in the ER [107], and impairs collagen deposition in a bile duct ligation-induced liver fibrosis mouse model [108]. However, no drug targeting Glt25d1 or Glt25d2 has been reported to date.
N-glycosylation, also present in collagens, remains not fully understood. It is possibly linked to the folding process of collagens. Interestingly, it seems dispensable for collagen secretion and assembly under normal conditions. However, it could prove beneficial under conditions of ER stress [109]. N-glycosylation has not been suggested as a target for regulating collagen levels or function within the corresponding pathological microenvironment.

4.5. Protein Folding

Protein disulfide isomerases (PDIs) constitute a family of endoplasmic reticulum-resident proteins that play a crucial role in the folding and assembly of proteins, including collagen [110]. Specifically, PDIs assist in the formation of the triple helix structure of collagens by catalyzing the proper formation of disulfide bonds, which are essential for stabilizing collagen molecules. One of them is P4HB (or PDI), a component of the prolyl-4-hydroxylase complex described above. Interestingly, PDI plays a relevant role in platelet activation and thrombosis, which could be regulated with known Pdi inhibitors. However, the role of collagen in the underlying mechanism appears to be tangential [111,112].
The analysis of recombinant collagen I-bound material from HT-1080 clones, conducted through quantitative mass spectrometry-based proteomics, unveiled a complex interactome, which included additional members of the PDI family that could serve as potential targets, such as Pdia3, Pdia4, Pdia6, Erp44, and others [113]. Multiple members of the PDI family have been associated with cancer. For instance, PDIA3 has been linked to cancer initiation, progression, and response to chemotherapy. It has also been identified as a potential therapeutic target in glioblastoma. Additionally, the Pdia3 inhibitor punicalagin has shown anti-glioblastoma activity in vitro [114]. However, there has been no reported evidence regarding the involvement of collagen in pathological mechanisms or the pharmacological activity of punicalagin.
Grp78 (HSPA5) and Grp94 (HSP90B1) are highly conserved molecular chaperones that interact with collagen within the secretory pathway [115]. Grp78, a central regulator of the unfolded protein response in the endoplasmic reticulum, has also been observed to be overexpressed in cancer, notably on the outer surface of the plasma membrane (csGrp78). This localization makes it susceptible to targeting with antibodies. A monoclonal immunoglobulin M antibody (PAT-SM6) to csGrp78 had a favorable safety profile (phase 1 clinical trial) in patients with relapsed and refractory multiple myeloma [116]; however, its definitive efficacy remains elusive. Grp78 could also be targeted with organic compounds with similar purposes [117]. Likewise, Grp94 has been detected on the outer surface of the plasma membrane and found to be upregulated in cancer. Several inhibitors, including antibodies, have been tested, showing promising results [118]. In both cases (Grp78 and Grp94), the relevance of collagen expression in their mechanism of action has not been examined.
FK506-binding proteins (FKBPs) were identified based on their ability to bind tacrolimus (or FK506), an immunosuppressive drug. FKBPs are peptidyl-prolyl isomerases, catalyzing the cis-trans isomerization of peptidyl-prolyl bonds in peptides and proteins [119]. FK506-binding protein 10 (FKBP10) resides in the ER and functions as a chaperone for collagen I [120]. A pathogenic mutation in FKBP10 inhibits the hydroxylation of lysine residues in the collagen telopeptide, which is essential for cross-linking, leading to osteogenesis imperfecta [121]. Downregulation of FKBP10 expression in idiopathic pulmonary fibrosis significantly decreases the levels of collagen I and collagen V [122]. To date, there are no drugs targeting FK506-binding protein 10 that have been reported to be effective in treating collagen-mediated diseases. Heat shock protein 47 (HSP47) transiently binds to procollagen in the ER and dissociates in the cis-Golgi or ER-Golgi intermediate compartment region (ERGIC). It plays a central role in fibrosis, and it is a relevant target to reduce collagen expression. Increased HSP47 in cardiac fibroblasts exacerbates fibrosis and cell proliferation in ischemic hearts. And the HSP47 inhibitor Col003 inhibits HR-induced fibrogenesis in vitro [123]. One of the most advanced drugs to date is BMS-986263, a lipid nanoparticle containing HSP47 siRNA. Patients with hepatic fibrosis secondary to HCV infection were administered once-weekly intravenous infusions of BMS-986263 for 12 weeks, demonstrating good tolerability and yielding promising results [124].

4.6. Protein Trafficking

Conventional COPII-dependent vesicles are primarily involved in transporting small cargo molecules from the ER to the Golgi apparatus. However, procollagen, being a large and bulky protein, requires specialized machinery and mechanisms for its export from the ER. Tango1 (MIA3) and cTAGE5 (MIA2) are proteins involved in facilitating the ER-Golgi trafficking of collagen. They play essential roles in the formation and function of ER exit sites (ERESs), where cargo is packaged into transport vesicles for delivery [125,126].
MIA3 knockout mice are defective in the sorting and export of several collagens, including I, II, III, IV, VII, and IX, and osteogenesis is compromised [127]. However, it is not exclusive to collagen [128]. Moreover, MIA3 binds neurturin (NRTN), activating hepatocellular carcinoma cell proliferation and EMT, likely through the activation of the PI3K/AKT/mTOR pathway [129].
Although no drugs have been discovered to target Tango1 directly, the recent characterization of the collagen IV-Tango1 interaction represents a significant advancement [130]. This understanding paves the way for the development of drugs specifically tailored to target collagen cargo.

4.7. Propeptide Cleavage

Fibrillar collagens are initially secreted with intact N- and C-terminal propeptides, which must be removed for their supramolecular assembly. Enzymes crucial for propeptide cleavage include bone morphogenetic protein 1 (BMP1) and tolloid-like 1 and 2 (TLL1 and TLL2). They belong to the astacin family of human metalloproteinases. This family targets several components of the extracellular matrix of both connective and epithelial tissues [131]. Importantly, BMP1 is not a growth factor like other BMPs, which are involved in the development and maintenance of various tissues (not just bones) [132].
BMP1 exhibits expression as several spliced isoforms, with antibodies targeting the BMP1-3 isoform proving effective in impairing CCl4-induced rat liver fibrosis [133]. Furthermore, organic compounds like UK383,367 have been shown to downregulate the maturation of procollagen I in vitro [134]. It has also demonstrated efficacy in reducing fibrosis and inflammation in a mouse model of chronic kidney disease induced by unilateral ureteral obstruction. Administration of the drug was performed intraperitoneally prior to surgery [135]. However, the relevance of the specific role of BMP1 in the pathogenesis of fibrosis has recently been questioned. This uncertainty arises from observations that BMP1 knockout mice develop fibrosis when treated with bleomycin, similar to control mice, despite BMP1 being overexpressed (in wild type) as observed in patients [136].
Other procollagen metalloproteinases are three members (ADAMTS2, ADAMTS3, and ADAMTS14) of the ‘a disintegrin-like and metalloprotease with thrombospondin type 1 motif’ (ADAMTS) family. This family encompasses a group of 19 members with diverse specific substrates, although not all of them have been fully characterized [137,138]. The absence of ADAMTS2 leads to the accumulation of unprocessed amino procollagen, indicating that it could be an important and accessible (extracellular) target to disrupt fibrillar collagen [137]. However, no compound targeting these enzymes has been described so far. Interestingly, several compounds targeting other members of the family have been identified, e.g., ADAMTS5, with promising results in osteoarthritis [139], suggesting that it is an option for other ADAMTS.

4.8. Supramolecular Assembly and Crosslinking of Fibrillar Collagens

The supramolecular assembly of collagen triple helices is a spontaneous process mediated by many interhelical interactions. The process is not fully understood, and several models have been proposed. Classical models suggest a direct cellular regulation of the process [140], with integrin-collagen interactions potentially influencing it [141]. Conversely, an alternative phase-transition model proposes that the protomers aggregate as a rapid self-assembly process because of their longitudinal structure, mechanical loading, and geometric confinement in intercellular channels [142]. The involvement of integrins or other collagen-interacting molecules in this process holds promise for potential novel pharmacological interventions in the future.
The final structure of collagen fibers relies on interprotomeric covalent bonding to stabilize the fibers, facilitated by the enzymatic deamination/oxidation of lysines. Members of the copper-dependent lysyl oxidase family (LOX1, LOXL1, LOXL2, LOXL3, and LOXL4) orchestrate this redox process: initially, LOX oxidatively deaminates lysine or hydroxylysine residues in collagen and elastin proteins, transforming them into allysine residues. Subsequently, two allysine residues condense in a variety of aldol dimers [143], which seems to be the major stable cross-linking bond at both ends of the type I collagen molecule in tissues that use the lysine aldehyde pathway [144]. However, it has been contested [145]. Classically, it had been stated that allysine aldols further react to produce histidinohydroxylysinonorleucine, which had been described as the main stable natural maturation product [146]. Interestingly, LOX is secreted as a proenzyme that is activated by BMP1 and ADAMTS2/14 [147].
These targets have been the most extensively assayed. In December 2010, Gilead Sciences acquired Arresto Biosciences for $225 million. Arresto Biosciences was the owner of simtuzumab (AB0024), a humanized monoclonal antibody targeting the human LOXL2. The antibody demonstrated efficacy in animal models of cancer and fibrosis [148]. Despite being subjected to 10 clinical trials and overall being well tolerated, its effectiveness remains elusive. Some of the clinical trials on AB0024 were for conditions including idiopathic pulmonary fibrosis [149], primary sclerosing cholangitis [150], primary myelofibrosis or secondary to polycythemia vera or essential thrombocythemia [151], bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis or cirrhosis due to non-alcoholic [152], liver fibrosis in HIV- and HCV-infected adults [153], steatohepatitis pancreatic adenocarcinoma (combined with gemcitabine) [154], or metastatic KRAS mutant colorectal cancer (combined with 5-fluorouracil, leucovorin, and irinotecan) [155], among others.
The ineffectiveness of AB0024 could result from the intracellular functions of LOXL2, which are likely distinct from its lysyl oxidase activity [156]. In this scenario, small-molecule inhibitors targeting LOXL2 have undergone testing in both pre-clinical and clinical trials. Among these, PAT-1251 has been investigated the most. However, a phase II clinical trial involving the LOXL2 inhibitor PAT-1251 was halted following the acquisition of the owner company by new investors [157].
Alternatively, the limited effectiveness of simtuzumab could be attributed to the activity of other lysyl oxidases. To address this, broad-spectrum LOX inhibitors such as PXS-5505 have been investigated. An open-label phase 1/2a study with 39 participants indicates that PXS-5505 is safe for patients diagnosed with primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis [158]. Although its efficacy has not been definitively demonstrated, preliminary results indicate promising inhibition of LOX and LOXL2 in vivo, suggesting a potential antifibrotic effect [159].
An additional clinical trial for PXS-5505 was terminated due to insufficient participation [160].

5. Indirect Targeting of Collagen IV: Protein Folding and Supramolecular Assembly

Each basal layer of an epithelial tissue rests on a basement membrane, which is its main component, type IV collagen.
The supramolecular assembly of type IV collagen depends on its carboxy-terminal NC1 (non-collagenous) and amino-terminal 7S domains. These domains are not proteolyzed and interact with similar domains of other protomers in the collagen IV network. The NC1 domain of two protomers interacts, forming a hexamer that is further stabilized by specific covalent bonds of sulfinimine (S=N), a cross-link of methionine and hydroxylysine residues [161].
The enzyme peroxidasin (PXDN), located within the basement membrane, generates hypohalous acid intermediates that oxidize methionine, leading to the formation of the sulfilimine cross-link. PXDN is also involved in the cross-linking of elastin. Its dysregulation has been associated with various pathological conditions [162]. The extracellular localization of PXDN, along with its relatively specific activity, renders this pharmacological approach particularly intriguing. Phloroglucinol, a known inhibitor of PXDN [163,164], emerges as a promising compound already formulated for other purposes since a daily intraperitoneal injection of phloroglucinol has been shown to reduce interstitial fibrosis in a mouse model of unilateral ureteral obstruction [165]. In vitro studies have recently identified new inhibitors of PXDN [166]. One noteworthy feature of collagen IV is its structural diversity. Differently folded NC1 variants lead to alternative assembly [14], which is potentially linked to the formation of collagen IV in the mesenchymal matrix. This mesenchymal collagen IV seems to be critical for the survival of cancerous cells undergoing EMT [15]. This alternative structure of collagen IV depends on GPBP (COL4A3BP) activity [15,30]. The GPBP inhibitor T12 is a terphenylic compound that mimics an interactive site, which facilitates the self-oligomerization of GPBP. Oral administration of T12 inhibits the growth of primary tumors and metastases of cancerous cells in an orthotopic and syngeneic murine model of triple-negative breast carcinoma [15].

6. Targeting with Collagen

Animal collagen and human recombinant collagen have been extensively used during the last two decades for aesthetic and general tissue repair purposes. Synthetic nanomaterials that mimic the structure and properties of natural collagens have been developed and display hemostatic activity [167]. As these matrices are not real drugs, they fall outside of the scope of the present review and will not be addressed here.
Whole collagen molecules are insoluble proteins that are far more difficult to use as biological drugs than antibodies. However, collagen fragments of lower molecular weight are more amenable to being used as drugs, and indeed, they have received significant attention in pharmacological studies. Enzymatic degradation of ECM proteins renders fragments named matrikines that have diverse biological activities [168]. Some of these protein fragments show exposed sites that are cryptic in the original whole polypeptides, so they are called matricryptins [169]. Different types of collagens have been identified as the original sources of matrikines and matricryptins. While some of these peptides have shown detrimental effects on health, others have been reported to be beneficial and have even been tested as potential therapeutic agents (Table 2).

6.1. Collagen I

One of the collagen-derived peptides with pharmacological activity is p1158/59, a 15-residue-long matricryptin produced by MMP-2/MMP-9 digestion of α1(I). Peptide p1158/59 is naturally present in human and mouse infarcted myocardium, and its synthetic counterpart has been shown to promote remodeling of left ventricle tissue and cardiac function in infarcted mouse hearts by mediating scarring and angiogenesis [170,171]. Peptide p1158/59 also potentiated the remodeling of the mouse aorta wall after induced thrombosis [172]. To our knowledge, p1158/59 has not yet entered clinical trials.

6.2. Collagen II

Gauci et al. [173] evidenced the existence of collagen II matrikines that promoted angiogenesis in ossification processes. The authors used a mouse knock-in approach in which the collagenase cleavage site in the α1(II) chain was mutated, thus impairing the possible generation of matrikines. The mutant mice showed abnormal ossification due to altered angiogenesis. The authors indicated their results suggested possible new approaches to enhance fracture healing, although they did not identify the pro-angiogenic collagen II matrikines whose existence they indirectly unveiled.

6.3. Collagen IV

The network-forming type IV collagen is one of the main components of basement membranes, and it is subjected to matrikine-releasing proteolytical processing. Arresten and canstatin are collagen IV-derived matrikines consisting of 26-kDa α1(IV) and 24-kDa α2(IV) C-terminal fragments, respectively. Both have shown antiangiogenic activity and have been proposed as anticancer therapies [174]. Arresten and canstatin were first described in 2000 as endogenous proteolytical fragments [175,176]. Arresten has been shown to reduce the invasiveness of squamous cell carcinoma in mice [177]. Canstatin has also been shown to prevent ventricular arrhythmia in an ischemia/reperfusion rat model, partly by inhibiting the production of reactive oxygen species and the elevation of intracellular Ca2+ levels [178]. Additionally, canstatin also protected the rat right ventricle from fibrotic remodeling induced by experimental pulmonary arterial hypertension, possibly by interfering with Ca2+/calcineurin pathways [179]. However, neither arresten nor canstatin has been tested in clinical trials so far.
Type IV collagen α3 chain [α3(IV)] proteolysis by MMPs releases the 28-kDa C-terminal noncollagenous 1 (NC1) domain known as tumstatin, which displays antiangiogenic activity due to interaction with αvβ3 integrin [180]. This antiangiogenic activity was mapped to tumstatin 74–98 residues or peptide T7 [181]. T7 peptide also showed cytotoxic activity mediated, at least in part, by impairment of autophagy [182]. It should be emphasized that the tumstatin-derived T7 peptide has no relation to the so-called T7 peptide that binds to the transferrin receptor, used for liposome delivery purposes [183].
Another tumstatin fragment with proven pharmacological activity is peptide T3, (residues 69–88). T3 improved heart function and reduced heart hypertrophy, fibrosis, and oxidative stress after myocardial infarction in rats [184]. In addition, T3 inhibited apoptosis in cardiomyoblasts [185], which further underscores its utility in myocardial protection.
In relation to clinical applications with tumstatin-based drugs, in 2023 Ocugen Inc. company submitted an Investigational New Drug (IND) application to initiate a Phase 1 clinical trial with OCU200 [186], a tumstatin-transferrin fusion polypeptide. OCU200 is proposed as a treatment for diabetic macular edema, and in preclinical studies, it inhibited endothelial cell proliferation and damage in an oxygen-induced retinopathy mouse model [187].
Tetrastatin is the α4(IV)NC1 domain and was initially reported to harbor limited or no antiangiogenic properties [188]. Nevertheless, a tetrastatin-derived peptide (tetrastatin-2) evidenced antiangiogenic activity [189]. Additionally, whole tretrastatin showed antitumor properties [190], which were mapped to a 13-residue sequence known as QS-13 [191]. QS-13 itself also showed the ability to inhibit endothelial cell migration in vitro and antiangiogenic activity in mice [192].
The whole α5(IV)NC1 domain apparently lacked antiangiogenic activity, according to early studies [188]. However, an endogenous 20-residue-long peptide contained within the α5(IV)NC1 domain (pentastatin-1) displayed antiangiogenic properties and inhibited tumor growth in xenograft experiments in mice [193]. Pentastatin-1 also caused endothelial dysfunction and arterial pressure increase in mice, suggesting it could have a role in pulmonary hypertension [194]. Weckmann et al. found that the full α5(IV)NC1 domain, named lamstatin by the authors, inhibited lymphangiogenesis (formation of new lymph vessels) induced by tumors in mice. The activity of lamstatin was mimicked by a 17-residue peptide (CP17) encompassing amino acids 66–82 of the whole α5(IV)NC1 domain [195].
The α6(IV)NC1 domain or hexastatin has shown antiangiogenic and antitumor activity [188,196], and it has been proposed as a possible treatment for eye diseases presenting choroidal neovascularization, such as the wet form of age-related macular degeneration [197].
Despite the mentioned scientific reports, as of April 2024 no drug based on the α4(IV)NC1, α5(IV)NC1, or α6(IV)NC1 domains have yet entered clinical trials, according to the ClinicalTrials.gov database.

6.4. Collagen VIII

Like collagen IV, type VIII collagen is a basement membrane component that undergoes matrikine-producing degradation. In a first report, the recombinant human α1(VIII) chain C-terminal NC1 domain or vastatin inhibited proliferation and induced apoptosis of bovine aortic endothelial cells in early results, suggesting it held antiangiogenic activity [198]. Later studies found that vastatin was a human endogenous matrikine whose expression was diminished in hepatocellular carcinoma patients and that recombinant vastatin inhibited angiogenesis, tumor growth, and metastasis in a rat model of hepatocellular carcinoma [199]. Additionally, using a mouse model of glioblastoma, the antiangiogenic properties of recombinant vastatin were confirmed, and its ability to extend survival was shown [200].

6.5. Collagen XVIII

The basement membrane-associated type XVIII collagen is the source of endostatin, a matrikine that has received major attention in the last three decades. Endostatin is the 20-kDa C-terminal fragment of α1(XVIII) chain, and it was originally identified as an endogenous antiangiogenic polypeptide that inhibited primary tumor and metastasis growth in mice [201]. The antiangiogenic properties of endostatin rely at least on the interference with the signaling pathways of vascular endothelial growth factor (VEGF) [202], integrins [203], and nucleolin [204] in endothelial cells. Endostatin-derived drugs have been significantly used in clinical trials. As of April 2024, in the ClinicalTrials.gov database, there are 19 interventional clinical trials registered as “completed” in which recombinant human endostatin has been used as anticancer therapy. In these trials, the drug most frequently used has been Endostar™, a recombinant human endostatin expressed in Escherichia coli as a fusion protein with a hexahistidine tag that eases purification and increases stability. Endostar™ was approved in China in 2005 as a therapy against non-small-cell lung cancer [205]. The plasma half-life of recombinant endostatin is short, so it was conjugated to polyethylene glycol (PEG) to improve its pharmacokinetic parameters [206]. PEGylated endostatin or M2ES has been used in clinical trials as an anticancer therapy [207], but as far as we know, its approval has not yet been granted.
Endostatin-derived short synthetic peptides are antiangiogenic [208,209] and display antitumor activity [210], thus mimicking the properties of the whole α1(XVIII) fragment. Additionally, the endostatin-derived E3 peptide (residues 133–180) reduced the TGFβ-induced fibrosis in mouse skin. The C-terminal amidation of E3 rendered an even more antifibrotic peptide (E4) that, unlike other endostatin-derived peptides, lacked antiangiogenic activity [211]. The E3 analog END55, engineered to increase stability and solubility and expressed in plants, reversed established lung and skin fibrosis induced by bleomycin in mice. END55 also reduced fibrosis markers in lung explants of human patients suffering from idiopathic pulmonary fibrosis [212].

6.6. Collagens XV and XIX

Type XV collagen is a multidomain proteoglycan localized to basement membrane zones [213]. The α1(XV) C-terminal domain, or restin, was described as a peptide with antiangiogenic and antitumor properties [214]. However, it was later reported that while whole collagen XV and peptides derived from the N-terminal and collagenous regions displayed antitumor activity, restin failed to inhibit cervical carcinoma cell proliferation in vivo [215].
Type XIX collagen is also a component of basement membranes, and the 19-amino acid C-terminal α1(XIX)NC1 domain holds antitumor properties mediated by its ability to inhibit cancer cell invasiveness and angiogenesis [216]. Experiments with a plasmin digestion product of collagen XIX containing most of the α1(XIX)NC1 domain (peptide F4) showed the antitumor activity was due to interaction with integrins αvβ3 and α5β1 [217,218].
Matrikines derived from collagens XV and XIX have received far less attention than endostatin, and no clinical trials using related drugs have been registered in the ClinicalTrials.gov database so far.

7. Epilogue: Gene Therapy

Recently, collagen-genetic diseases have been tackled with gene therapy approaches.
In 2023, the US FDA approved Beremagene Geperpavec for the treatment of recessive dystrophic epidermolysis bullosa (RDEB), a monogenic disease caused by mutations in COL7A1 [219,220]. Other companies are currently developing treatments against RDEB based on recombinant expression of type VII collagen. Abeona Therapeutics has carried out clinical trials with prademagene zamikeracel (pz-cel) [221], an autologous cell therapy in which keratinocytes collected from recessive DEB patients are ex vivo engineered to express recombinant α1(VII) and transferred back to the patients. Gene delivery to patient keratinocytes is performed by transduction with a retrovirus containing the full-length α1(VII) cDNA [222,223]. Other genetic therapies are being developed against RDEB. The CRISPR/Cas9 system has been used to correct COL7A1 frameshift mutations in fibroblasts from RDEB patients [224] and to delete mutant COL7A1 exons in patient keratinocytes [225]. The more recently developed CRISPR/Cas9 nickase (Cas9n) system can introduce highly specific modifications in DNA while significantly avoiding off-target alterations and allowing the correction of single base substitutions, deletions, and insertions [226] The base editing and prime editing CRISPR/Cas9n systems, which rely on the expression of Cas9n fused to a base editing enzyme or to reverse transcriptase, respectively, have been used to correct several COL7A1 gene mutations in DEB patient fibroblasts [227]. Junctional epidermolysis bullosa (JEB) is a hereditary disease that may be caused by mutations in the COL17A1 gene, coding for type XVII collagen α1 chain [α1(XVII)] [228]. Several gene therapy-based efforts to treat JEB have been carried out. An autologous cell therapy with patient skin cells genetically modified to express recombinant α1(XVII) from a retroviral vector was used in a clinical trial [229], but the trial was terminated prior to completion. A CRISPR/Cas9-based approach was performed to correct a COL17A1 frameshift mutation in cultured JEB keratinocytes by homology-directed repair [230]. Reframing of COL17A1 has also been achieved by CRISPR/Cas9 nickase-based paired nicking [231]. However, although the CRISPR/Cas9 nickase system has reduced the rate of off-target alterations in the original CRISPR/Cas9 nuclease system, the risk of the appearance of unwanted genomic alterations persists [232].
Finally, gene therapy treatments against osteogenesis imperfecta (OI) caused by mutations in type I collagen genes are also being developed. Working with an OI mouse model and using adeno-associated virus (AAV) for delivery purposes, Yang et al. carried out a CRISPR/Cas9, homology-directed repair approach to correct OI-causing Col1a2 mutations in vivo, and they reported an amelioration of the animal phenotypes [233].

8. Conclusions

The overall effectiveness of targeting collagen and of targeting with collagen-based therapies is currently limited (Table 3). Only a few drugs have shown success in clinical trials, and their applications are restricted to a limited number of diseases. A key challenge when targeting collagen-related pathways for a particular pathological condition is specificity. However, ongoing research focused on understanding specific collagen isoforms, their interactions, and the underlying molecular mechanisms of collagen-related diseases holds promise. By gaining a deeper understanding of these factors, it may be possible to develop more precise therapeutic interventions. In this sense, a disease-specific diversification of collagen I has been described [234]. And recombinant collagen IV exhibits a similar phenomenon of structural diversification [16]. It could pave the way for monoclonal antibodies designed to target these disease-specific collagen formations. These targeted treatments have the potential to offer improved efficacy and fewer adverse effects, addressing the current limitations of collagen pharmacology.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/ijms25126523/s1.

Author Contributions

Conceptualization, F.R. and F.R.-R.; software, J.A.P.-R., I.V. and F.R.; writing—original draft preparation, F.R., F.R.-R. and J.M.H.-A.; writing—review, editing and visualization J.A.P.-R., J.M.H.-A., F.R.-R., I.V. and F.R.; funding acquisition, J.M.H.-A. and J.A.P.-R. All authors have read and agreed to the published version of the manuscript.

Funding

Centro de Investigación Translacional San Alberto Magno of the Universidad Católica de Valencia San Vicente Mártir.

Acknowledgments

Our gratitude to Juan Saus, our master and guiding mentor, as well as to Billy G. Hudson and Jörgen Wieslander, whose shared enthusiasm for science and collagen has been invaluable.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Ricard-Blum, S. The Collagen Family. Cold Spring Harb. Perspect. Biol. 2011, 3, a004978. [Google Scholar] [CrossRef] [PubMed]
  2. Nishimura, I.; Muragaki, Y.; Olsen, B.R. Tissue-Specific Forms of Type IX Collagen-Proteoglycan Arise from the Use of Two Widely Separated Promoters. J. Biol. Chem. 1989, 264, 20033–20041. [Google Scholar] [CrossRef]
  3. Heljasvaara, R.; Aikio, M.; Ruotsalainen, H.; Pihlajaniemi, T. Collagen XVIII in Tissue Homeostasis and Dysregulation—Lessons Learned from Model Organisms and Human Patients. Matrix Biol. 2017, 57–58, 55–75. [Google Scholar] [CrossRef]
  4. McAlinden, A.; Havlioglu, N.; Liang, L.; Davies, S.R.; Sandell, L.J. Alternative Splicing of Type II Procollagen Exon 2 Is Regulated by the Combination of a Weak 5′ Splice Site and an Adjacent Intronic Stem-Loop Cis Element. J. Biol. Chem. 2005, 280, 32700–32711. [Google Scholar] [CrossRef]
  5. Van Der Rest, M.; Mayne, R. Type IX Collagen Proteoglycan from Cartilage Is Covalently Cross-Linked to Type II Collagen. J. Biol. Chem. 1988, 263, 1615–1618. [Google Scholar] [CrossRef]
  6. Koch, M.; Bernasconi, C.; Chiquet, M. A Major Oligomeric Fibroblast Proteoglycan Identified as a Novel Large Form of Type-XII Collagen. Eur. J. Biochem. 1992, 207, 847–856. [Google Scholar] [CrossRef]
  7. Ehnis, T.; Dieterich, W.; Bauer, M.; Kresse, H.; Schuppan, D. Localization of a Binding Site for the Proteoglycan Decorin on Collagen XIV (Undulin). J. Biol. Chem. 1997, 272, 20414–20419. [Google Scholar] [CrossRef] [PubMed]
  8. Myers, J.C.; Amenta, P.S.; Dion, A.S.; Sciancalepore, J.P.; Nagaswami, C.; Weisel, J.W.; Yurchenco, P.D. The Molecular Structure of Human Tissue Type XV Presents a Unique Conformation among the Collagens. Biochem. J. 2007, 404, 535–544. [Google Scholar] [CrossRef] [PubMed]
  9. Halfter, W.; Dong, S.; Schurer, B.; Cole, G.J. Collagen XVIII Is a Basement Membrane Heparan Sulfate Proteoglycan. J. Biol. Chem. 1998, 273, 25404–25412. [Google Scholar] [CrossRef]
  10. Callebaut, I.; Mignotte, V.; Souchet, M.; Mornon, J.-P. EMI Domains Are Widespread and Reveal the Probable Orthologs of the Caenorhabditis Elegans CED-1 Protein. Biochem. Biophys. Res. Commun. 2003, 300, 619–623. [Google Scholar] [CrossRef]
  11. Ye, J.J.; Bian, X.; Lim, J.; Medzhitov, R. Adiponectin and Related C1q/TNF-Related Proteins Bind Selectively to Anionic Phospholipids and Sphingolipids. Proc. Natl. Acad. Sci. USA 2020, 117, 17381–17388. [Google Scholar] [CrossRef] [PubMed]
  12. Fidler, A.L.; Darris, C.E.; Chetyrkin, S.V.; Pedchenko, V.K.; Boudko, S.P.; Brown, K.L.; Gray Jerome, W.; Hudson, J.K.; Rokas, A.; Hudson, B.G. Collagen IV and Basement Membrane at the Evolutionary Dawn of Metazoan Tissues. eLife 2017, 6, e24176. [Google Scholar] [CrossRef] [PubMed]
  13. Fidler, A.L.; Boudko, S.P.; Rokas, A.; Hudson, B.G. The Triple Helix of Collagens—An Ancient Protein Structure That Enabled Animal Multicellularity and Tissue Evolution. J. Cell Sci. 2018, 131, jcs203950. [Google Scholar] [CrossRef] [PubMed]
  14. Calvete, J.J.; Revert, F.; Blanco, M.; Cervera, J.; Tárrega, C.; Sanz, L.; Revert-Ros, F.; Granero, F.; Pérez-Payá, E.; Hudson, B.G.; et al. Conformational Diversity of the Goodpasture Antigen, the Noncollagenous-1 Domain of the A3 Chain of Collagen IV. Proteomics 2006, 6, S237–S244. [Google Scholar] [CrossRef]
  15. Revert, F.; Revert-Ros, F.; Blasco, R.; Artigot, A.; López-Pascual, E.; Gozalbo-Rovira, R.; Ventura, I.; Gutiérrez-Carbonell, E.; Roda, N.; Ruíz-Sanchis, D.; et al. Selective Targeting of Collagen IV in the Cancer Cell Microenvironment Reduces Tumor Burden. Oncotarget 2018, 9, 11020. [Google Scholar] [CrossRef] [PubMed]
  16. Casino, P.; Gozalbo-Rovira, R.; Rodríguez-Díaz, J.; Banerjee, S.; Boutaud, A.; Rubio, V.; Hudson, B.G.; Saus, J.; Cervera, J.; Marina, A. Structures of Collagen IV Globular Domains: Insight into Associated Pathologies, Folding and Network Assembly. IUCrJ 2018, 5, 765–779. [Google Scholar] [CrossRef] [PubMed]
  17. Antar, S.A.; Ashour, N.A.; Marawan, M.E.; Al-Karmalawy, A.A. Fibrosis: Types, Effects, Markers, Mechanisms for Disease Progression, and Its Relation with Oxidative Stress, Immunity, and Inflammation. Int. J. Mol. Sci. 2023, 24, 4004. [Google Scholar] [CrossRef] [PubMed]
  18. Kasashima, H.; Duran, A.; Martinez-Ordoñez, A.; Nakanishi, Y.; Kinoshita, H.; Linares, J.F.; Reina-Campos, M.; Kudo, Y.; L’Hermitte, A.; Yashiro, M.; et al. Stromal SOX2 Upregulation Promotes Tumorigenesis through the Generation of a SFRP1/2-Expressing Cancer-Associated Fibroblast Population. Dev. Cell 2021, 56, 95–110.e10. [Google Scholar] [CrossRef] [PubMed]
  19. Wynn, T.A.; Ramalingam, T.R. Mechanisms of Fibrosis: Therapeutic Translation for Fibrotic Disease. Nat. Med. 2012, 18, 1028–1040. [Google Scholar] [CrossRef]
  20. Jessen, H.; Hoyer, N.; Prior, T.S.; Frederiksen, P.; Karsdal, M.A.; Leeming, D.J.; Bendstrup, E.; Sand, J.M.B.; Shaker, S.B. Turnover of Type I and III Collagen Predicts Progression of Idiopathic Pulmonary Fibrosis. Respir. Res. 2021, 22, 205. [Google Scholar] [CrossRef]
  21. Savin, I.A.; Zenkova, M.A.; Sen’kova, A.V. Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches. Int. J. Mol. Sci. 2022, 23, 14959. [Google Scholar] [CrossRef] [PubMed]
  22. Dutta, A.; Jayasinghe, G.; Deore, S.; Wahed, K.; Bhan, K.; Bakti, N.; Singh, B. Dupuytren’s Contracture–Current Concepts. J. Clin. Orthop. Trauma 2020, 11, 590–596. [Google Scholar] [CrossRef] [PubMed]
  23. Sharma, K.L.; Alom, M.; Trost, L. The Etiology of Peyronie’s Disease: Pathogenesis and Genetic Contributions. Sex. Med. Rev. 2020, 8, 314–323. [Google Scholar] [CrossRef] [PubMed]
  24. Roehlen, N.; Crouchet, E.; Baumert, T.F. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020, 9, 875. [Google Scholar] [CrossRef] [PubMed]
  25. Huang, C.; Iovanna, J.; Santofimia-Castaño, P. Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer. Int. J. Mol. Sci. 2021, 22, 4970. [Google Scholar] [CrossRef] [PubMed]
  26. Frangogiannis, N.G. Cardiac Fibrosis. Cardiovasc. Res. 2020, 117, 1450–1488. [Google Scholar] [CrossRef]
  27. Simões, F.C.; Cahill, T.J.; Kenyon, A.; Gavriouchkina, D.; Vieira, J.M.; Sun, X.; Pezzolla, D.; Ravaud, C.; Masmanian, E.; Weinberger, M.; et al. Macrophages Directly Contribute Collagen to Scar Formation during Zebrafish Heart Regeneration and Mouse Heart Repair. Nat. Commun. 2020, 11, 600. [Google Scholar] [CrossRef]
  28. Sobolewski, P.; Maślińska, M.; Wieczorek, M.; Łagun, Z.; Malewska, A.; Roszkiewicz, M.; Nitskovich, R.; Szymańska, E.; Walecka, I. Systemic Sclerosis–Multidisciplinary Disease: Clinical Features and Treatment. Reumatologia 2019, 57, 221–233. [Google Scholar] [CrossRef]
  29. Andrews, J.P.; Marttala, J.; Macarak, E.; Rosenbloom, J.; Uitto, J. Keloids: The Paradigm of Skin Fibrosis—Pathomechanisms and Treatment. Matrix Biol. 2016, 51, 37–46. [Google Scholar] [CrossRef]
  30. Revert, F.; Merino, R.; Monteagudo, C.; Macias, J.; Peydró, A.; Alcácer, J.; Muniesa, P.; Marquina, R.; Blanco, M.; Iglesias, M. Increased Goodpasture Antigen-Binding Protein Expression Induces Type IV Collagen Disorganization and Deposit of Immunoglobulin A in Glomerular Basement Membrane. Am. J. Pathol. 2007, 171, 1419–1430. [Google Scholar] [CrossRef]
  31. Bülow, R.D.; Boor, P. Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold. J. Histochem. Cytochem. 2019, 67, 643–661. [Google Scholar] [CrossRef]
  32. Zhang, J.; Liu, J.; Zhang, H.; Wang, J.; Hua, H.; Jiang, Y. The Role of Network-Forming Collagens in Cancer Progression. Int. J. Cancer 2022, 151, 833–842. [Google Scholar] [CrossRef] [PubMed]
  33. Bourgot, I.; Primac, I.; Louis, T.; Noël, A.; Maquoi, E. Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis. Front. Oncol. 2020, 10, 1488. [Google Scholar] [CrossRef]
  34. De Martino, D.; Bravo-Cordero, J.J. Collagens in Cancer: Structural Regulators and Guardians of Cancer Progression. Cancer Res. 2023, 83, 1386–1392. [Google Scholar] [CrossRef]
  35. Brisson, B.K.; Mauldin, E.A.; Lei, W.; Vogel, L.K.; Power, A.M.; Lo, A.; Dopkin, D.; Khanna, C.; Wells, R.G.; Puré, E.; et al. Type III Collagen Directs Stromal Organization and Limits Metastasis in a Murine Model of Breast Cancer. Am. J. Pathol. 2015, 185, 1471–1486. [Google Scholar] [CrossRef] [PubMed]
  36. Di Martino, J.S.; Nobre, A.R.; Mondal, C.; Taha, I.; Farias, E.F.; Fertig, E.J.; Naba, A.; Aguirre-Ghiso, J.A.; Bravo-Cordero, J.J. A Tumor-Derived Type III Collagen-Rich ECM Niche Regulates Tumor Cell Dormancy. Nat. Cancer 2022, 3, 90–107. [Google Scholar] [CrossRef] [PubMed]
  37. Slobodianuk, T.L.; Kochelek, C.; Foeckler, J.; Kalloway, S.; Weiler, H.; Flood, V.H. Defective Collagen Binding and Increased Bleeding in a Murine Model of von Willebrand Disease Affecting Collagen IV Binding. J. Thromb. Haemost. 2019, 17, 63–71. [Google Scholar] [CrossRef]
  38. Pareti, F.I.; Niiya, K.; McPherson, J.M.; Ruggeri, Z.M. Isolation and Characterization of Two Domains of Human von Willebrand Factor That Interact with Fibrillar Collagen Types I and III. J. Biol. Chem. 1987, 262, 13835–13841. [Google Scholar] [CrossRef]
  39. Lamandé, S.R.; Bateman, J.F. Genetic Disorders of the Extracellular Matrix. Anat. Rec. 2020, 303, 1527–1542. [Google Scholar] [CrossRef]
  40. Marom, R.; Rabenhorst, B.M.; Morello, R. Osteogenesis Imperfecta: An Update on Clinical Features and Therapies. Eur. J. Endocrinol. 2020, 183, R95–R106. [Google Scholar] [CrossRef]
  41. Has, C.; Bauer, J.W.; Bodemer, C.; Bolling, M.C.; Bruckner-Tuderman, L.; Diem, A.; Fine, J.-D.; Heagerty, A.; Hovnanian, A.; Marinkovich, M.P.; et al. Consensus Reclassification of Inherited Epidermolysis Bullosa and Other Disorders with Skin Fragility. Br. J. Dermatol. 2020, 183, 614–627. [Google Scholar] [CrossRef] [PubMed]
  42. Badalamente, M.A.; Hurst, L.C.; Benhaim, P.; Cohen, B.M. Efficacy and Safety of Collagenase Clostridium Histolyticum in the Treatment of Proximal Interphalangeal Joints in Dupuytren Contracture: Combined Analysis of 4 Phase 3 Clinical Trials. J. Hand. Surg. Am. 2015, 40, 975–983. [Google Scholar] [CrossRef] [PubMed]
  43. Cerveró, R.; Vazquez-Ferreiro, P.; Gómez-Herrero, D.; Carrera-Hueso, F.J.; Fikri-Banbrahim, N. Evolución al Año de Tratamiento Con CCH Para La Contractura de Dupuytren: Estudio Prospectivo. Rev. Esp. Cir. Ortop. Traumatol. 2018, 62, 448–457. [Google Scholar] [CrossRef] [PubMed]
  44. Zarb, R.M.; Graf, A.R.; Talhelm, J.E.; Stehr, R.C.; Sanger, J.R.; Matloub, H.S.; Daley, R.A. Dupuytren’s Contracture Recurrence and Treatment Following Collagenase Clostridium Histolyticum Injection: A Longitudinal Assessment in a Veteran Population. Mil. Med. 2023, 188, e2975–e2981. [Google Scholar] [CrossRef] [PubMed]
  45. Teloken, P.; Katz, D. Medical Management of Peyronie’s Disease: Review of the Clinical Evidence. Med. Sci. 2019, 7, 96. [Google Scholar] [CrossRef] [PubMed]
  46. Xiapex | European Medicines Agency. Document: EMA/95504/2020. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/xiapex (accessed on 31 May 2024).
  47. Endo Pharmaceuticals. A Phase 2B, Open-Label Study to Explore Tissue Histopathology Following Subcutaneous Injection of Collagenase Clostridium Histolyticum Using an Abdominoplasty Model. clinicaltrials.gov, 2022. Available online: https://www.clinicaltrials.gov/search?term=NCT04236635 (accessed on 7 June 2024).
  48. Fitzpatrick, J.; Richardson, C.; Klaber, I.; Richardson, M.D. Clostridium Histolyticum (AA4500) for the Treatment of Adhesive Capsulitis of the Shoulder: A Randomised Double-Blind, Placebo-Controlled Study for the Safety and Efficacy of Collagenase-Single Site Report. Drug Des. Dev. Ther. 2020, 14, 2707–2713. [Google Scholar] [CrossRef] [PubMed]
  49. García-Olmo, D.; Villarejo Campos, P.; Barambio, J.; Gomez-Heras, S.G.; Vega-Clemente, L.; Olmedillas-Lopez, S.; Guadalajara, H.; Garcia-Arranz, M. Intraperitoneal Collagenase as a Novel Therapeutic Approach in an Experimental Model of Colorectal Peritoneal Carcinomatosis. Sci. Rep. 2021, 11, 503. [Google Scholar] [CrossRef] [PubMed]
  50. Dolor, A.; Szoka, F. Digesting a Path Forward: The Utility of Collagenase Tumor Treatment for Improved Drug Delivery. Mol. Pharm. 2018, 15, 2069–2083. [Google Scholar] [CrossRef] [PubMed]
  51. Sheets, A.R.; Demidova-Rice, T.N.; Shi, L.; Ronfard, V.; Grover, K.V.; Herman, I.M. Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A Role for Collagenase from Santyl® Ointment in Post-Debridement Wound Healing? PLoS ONE 2016, 11, e0159598. [Google Scholar] [CrossRef]
  52. Das, A.; Datta, S.; Roche, E.; Chaffee, S.; Jose, E.; Shi, L.; Grover, K.; Khanna, S.; Sen, C.K.; Roy, S. Novel Mechanisms of Collagenase Santyl Ointment (CSO) in Wound Macrophage Polarization and Resolution of Wound Inflammation. Sci. Rep. 2018, 8, 1696. [Google Scholar] [CrossRef]
  53. Evrosimovska Andonovska, B.; Boris, V.; Dimova, C.; Veleska, D. Matrix Metalloproteinases (with Accent to Collagenases). J. Cell Anim. Biol. 2011, 5, 113–120. [Google Scholar]
  54. Cabral-Pacheco, G.A.; Garza-Veloz, I.; Castruita-De la Rosa, C.; Ramirez-Acuña, J.M.; Perez-Romero, B.A.; Guerrero-Rodriguez, J.F.; Martinez-Avila, N.; Martinez-Fierro, M.L. The Roles of Matrix Metalloproteinases and Their Inhibitors in Human Diseases. Int. J. Mol. Sci. 2020, 21, 9739. [Google Scholar] [CrossRef] [PubMed]
  55. Verma, R.P.; Hansch, C. Matrix Metalloproteinases (MMPs): Chemical-Biological Functions and (Q)SARs. Bioorg. Med. Chem. 2007, 15, 2223–2268. [Google Scholar] [CrossRef] [PubMed]
  56. Winer, A.; Adams, S.; Mignatti, P. Matrix Metalloproteinase Inhibitors in Cancer Therapy: Turning Past Failures into Future Successes. Mol. Cancer Ther. 2018, 17, 1147–1155. [Google Scholar] [CrossRef] [PubMed]
  57. Shah, M.A.; Bodoky, G.; Starodub, A.; Cunningham, D.; Yip, D.; Wainberg, Z.A.; Bendell, J.; Thai, D.; He, J.; Bhargava, P.; et al. Phase III Study to Evaluate Efficacy and Safety of Andecaliximab With mFOLFOX6 as First-Line Treatment in Patients With Advanced Gastric or GEJ Adenocarcinoma (GAMMA-1). J. Clin. Oncol. 2021, 39, 990–1000. [Google Scholar] [CrossRef] [PubMed]
  58. Shah, M.A.; Cunningham, D.; Metges, J.-P.; Van Cutsem, E.; Wainberg, Z.; Elboudwarej, E.; Lin, K.-W.; Turner, S.; Zavodovskaya, M.; Inzunza, D.; et al. Randomized, Open-Label, Phase 2 Study of Andecaliximab plus Nivolumab versus Nivolumab Alone in Advanced Gastric Cancer Identifies Biomarkers Associated with Survival. J. Immunother. Cancer 2021, 9, e003580. [Google Scholar] [CrossRef] [PubMed]
  59. Schreiber, S.; Siegel, C.A.; Friedenberg, K.A.; Younes, Z.H.; Seidler, U.; Bhandari, B.R.; Wang, K.; Wendt, E.; McKevitt, M.; Zhao, S.; et al. A Phase 2, Randomized, Placebo-Controlled Study Evaluating Matrix Metalloproteinase-9 Inhibitor, Andecaliximab, in Patients With Moderately to Severely Active Crohn’s Disease. J. Crohns Colitis 2018, 12, 1014–1020. [Google Scholar] [CrossRef] [PubMed]
  60. Addi, C.; Murschel, F.; De Crescenzo, G. Design and Use of Chimeric Proteins Containing a Collagen-Binding Domain for Wound Healing and Bone Regeneration. Tissue Eng. Part B Rev. 2016, 23, 163–182. [Google Scholar] [CrossRef] [PubMed]
  61. Ingham, K.; Brew, S.; Isaacs, B. Interaction of Fibronectin and Its Gelatin-Binding Domains with Fluorescent-Labeled Chains of Type I Collagen. J. Biol. Chem. 1988, 263, 4624–4628. [Google Scholar] [CrossRef]
  62. An, B.; Abbonante, V.; Yigit, S.; Balduini, A.; Kaplan, D.L.; Brodsky, B. Definition of the Native and Denatured Type II Collagen Binding Site for Fibronectin Using a Recombinant Collagen System. J. Biol. Chem. 2014, 289, 4941–4951. [Google Scholar] [CrossRef]
  63. Patten, J.; Wang, K. Fibronectin in Development and Wound Healing. Adv. Drug Deliv. Rev. 2020, 170, 353–368. [Google Scholar] [CrossRef] [PubMed]
  64. Yee, A.; Gildersleeve, R.; Gu, S.; Kretz, C.; McGee, B.; Carr, K.; Pipe, S.; Ginsburg, D. A von Willebrand Factor Fragment Containing the D’D3 Domains Is Sufficient to Stabilize Coagulation Factor VIII in Mice. Blood 2014, 124, 445–452. [Google Scholar] [CrossRef] [PubMed]
  65. Bergmeier, W.; Hynes, R.O. Extracellular Matrix Proteins in Hemostasis and Thrombosis. Cold Spring Harb. Perspect. Biol. 2012, 4, a005132. [Google Scholar] [CrossRef]
  66. Tan, H.; Song, Y.; Jin, J.; Zhao, X.; Chen, J.; Qing, Z.; Yu, S.; Huang, L. vWF A3-GPI Modification of EPCs Accelerates Reendothelialization of Injured Vessels via Collagen Targeting in Mice. J. Drug Target. 2016, 24, 744–751. [Google Scholar] [CrossRef]
  67. Ishihara, J.; Ishihara, A.; Sasaki, K.; Lee, S.S.-Y.; Williford, J.-M.; Yasui, M.; Abe, H.; Potin, L.; Hosseinchi, P.; Fukunaga, K.; et al. Targeted Antibody and Cytokine Cancer Immunotherapies through Collagen Affinity. Sci. Transl. Med. 2019, 11, eaau3259. [Google Scholar] [CrossRef] [PubMed]
  68. Dewerchin, M.; Carmeliet, P. PlGF: A Multitasking Cytokine with Disease-Restricted Activity. Cold Spring Harb. Perspect. Med. 2012, 2, a011056. [Google Scholar] [CrossRef]
  69. Martino, M.; Briquez, P.; Guc, E.; Tortelli, F.; Kilarski, W.; Metzger, S.; Rice, J.; Kuhn, G.; Müller, R.; Swartz, M.; et al. Growth Factors Engineered for Super-Affinity to the Extracellular Matrix Enhance Tissue Healing. Science 2014, 343, 885–888. [Google Scholar] [CrossRef] [PubMed]
  70. de Souza, S.J.; Brentani, R. Collagen Binding Site in Collagenase Can Be Determined Using the Concept of Sense-Antisense Peptide Interactions. J. Biol. Chem. 1992, 267, 13763–13767. [Google Scholar] [CrossRef]
  71. Chen, B.; Lin, H.; Wang, J.; Zhao, Y.; Wang, B.; Zhao, W.; Sun, W.; Dai, J. Homogeneous Osteogenesis and Bone Regeneration by Demineralized Bone Matrix Loading with Collagen-Targeting Bone Morphogenetic Protein-2. Biomaterials 2007, 28, 1027–1035. [Google Scholar] [CrossRef]
  72. Yu, S.; Li, Y.; Kim, D. Collagen Mimetic Peptides: Progress Towards Functional Applications. Soft Matter. 2011, 7, 7927–7938. [Google Scholar] [CrossRef]
  73. Chakravarti, S.; Stallings, R.L.; SundarRaj, N.; Cornuet, P.K.; Hassell, J.R. Primary Structure of Human Lumican (Keratan Sulfate Proteoglycan) and Localization of the Gene (LUM) to Chromosome 12q21.3-Q22. Genomics 1995, 27, 481–488. [Google Scholar] [CrossRef] [PubMed]
  74. Wang, K.; Wang, Y.; Cao, Y.; Wang, H.; Zhou, Y.; Gao, L.; Zeng, Z.; Cheng, M.; Jin, X.; Chen, J.; et al. Lumican Is Elevated in the Lung in Human and Experimental Acute Respiratory Distress Syndrome and Promotes Early Fibrotic Responses to Lung Injury. J. Transl. Med. 2022, 20, 392. [Google Scholar] [CrossRef] [PubMed]
  75. Momin, N.; Mehta, N.K.; Bennett, N.R.; Ma, L.; Palmeri, J.R.; Chinn, M.M.; Lutz, E.A.; Kang, B.; Irvine, D.J.; Spranger, S.; et al. Anchoring of Intratumorally Administered Cytokines to Collagen Safely Potentiates Systemic Cancer Immunotherapy. Sci. Transl. Med. 2019, 11, eaaw2614. [Google Scholar] [CrossRef] [PubMed]
  76. Avilés-Reyes, A.; Miller, J.H.; Lemos, J.A.; Abranches, J. Collagen-Binding Proteins of Streptococcus Mutans and Related Streptococci. Mol. Oral Microbiol. 2017, 32, 89–106. [Google Scholar] [CrossRef] [PubMed]
  77. Hulme, J.T.; D’Souza, W.N.; McBride, H.J.; Yoon, B.-R.P.; Willee, A.M.; Duguay, A.; Thomas, M.; Fan, B.; Dayao, M.R.; Rottman, J.B.; et al. Novel Protein Therapeutic Joint Retention Strategy Based on Collagen-Binding Avimers. J. Orthop. Res. 2018, 36, 1238–1247. [Google Scholar] [CrossRef] [PubMed]
  78. Zhang, Y.; Stefanovic, B. mTORC1 Phosphorylates LARP6 to Stimulate Type I Collagen Expression. Sci. Rep. 2017, 7, 41173. [Google Scholar] [CrossRef] [PubMed]
  79. Stefanovic, B.; Manojlovic, Z.; Vied, C.; Badger, C.-D.; Stefanovic, L. Discovery and Evaluation of Inhibitor of LARP6 as Specific Antifibrotic Compound. Sci. Rep. 2019, 9, 326. [Google Scholar] [CrossRef] [PubMed]
  80. Szwed, A.; Kim, E.; Jacinto, E. Regulation and Metabolic Functions of mTORC1 and mTORC2. Physiol. Rev. 2021, 101, 1371–1426. [Google Scholar] [CrossRef] [PubMed]
  81. Verdura, S.; Cuyàs, E.; Ruiz-Torres, V.; Micol, V.; Joven, J.; Bosch-Barrera, J.; Menendez, J.A. Lung Cancer Management with Silibinin: A Historical and Translational Perspective. Pharmaceuticals 2021, 14, 559. [Google Scholar] [CrossRef]
  82. Choi, S.; Ham, S.; Lee, Y.I.; Kim, J.; Lee, W.J.; Lee, J.H. Silibinin Downregulates Types I and III Collagen Expression via Suppression of the mTOR Signaling Pathway. Int. J. Mol. Sci. 2023, 24, 14386. [Google Scholar] [CrossRef]
  83. Suzuki, H.I. Roles of MicroRNAs in Disease Biology. JMA J. 2023, 6, 104–113. [Google Scholar] [CrossRef]
  84. Cushing, L.; Kuang, P.P.; Qian, J.; Shao, F.; Wu, J.; Little, F.; Thannickal, V.J.; Cardoso, W.V.; Lü, J. miR-29 Is a Major Regulator of Genes Associated with Pulmonary Fibrosis. Am. J. Respir. Cell Mol. Biol. 2011, 45, 287–294. [Google Scholar] [CrossRef] [PubMed]
  85. Tang, X.; Liu, L.; Liu, S.; Song, S.; Li, H. MicroRNA-29a Inhibits Collagen Expression and Induces Apoptosis in Human Fetal Scleral Fibroblasts by Targeting the Hsp47/Smad3 Signaling Pathway. Exp. Eye Res. 2022, 225, 109275. [Google Scholar] [CrossRef]
  86. Cushing, L.; Kuang, P.; Lü, J. The Role of miR-29 in Pulmonary Fibrosis. Biochem. Cell Biol. 2015, 93, 109–118. [Google Scholar] [CrossRef]
  87. Matsumoto, Y.; Itami, S.; Kuroda, M.; Yoshizato, K.; Kawada, N.; Murakami, Y. MiR-29a Assists in Preventing the Activation of Human Stellate Cells and Promotes Recovery From Liver Fibrosis in Mice. Mol. Ther. 2016, 24, 1848–1859. [Google Scholar] [CrossRef] [PubMed]
  88. Chioccioli, M.; Roy, S.; Newell, R.; Pestano, L.; Dickinson, B.; Rigby, K.; Herazo-Maya, J.; Jenkins, G.; Ian, S.; Saini, G.; et al. A Lung Targeted miR-29 Mimic as a Therapy for Pulmonary Fibrosis. eBioMedicine 2022, 85, 104304. [Google Scholar] [CrossRef]
  89. miRagen Therapeutics, Inc. A Phase 2, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy, Safety and Tolerability of MRG-201 Following Intradermal Injection in Subjects With a History of Keloids. clinicaltrials.gov, 2021. Available online: https://www.clinicaltrials.gov/search?term=NCT03601052 (accessed on 7 June 2024).
  90. Devos, H.; Zoidakis, J.; Roubelakis, M.; Latosinska, A.; Vlahou, A. Reviewing the Regulators of COL1A1. Int. J. Mol. Sci. 2023, 24, 10004. [Google Scholar] [CrossRef] [PubMed]
  91. Lo, C.-H.; Li, L.-C.; Yang, S.-F.; Tsai, C.-F.; Chuang, Y.-T.; Chu, H.-J.; Ueng, K.-C. MicroRNA Let-7a, -7e and -133a Attenuate Hypoxia-Induced Atrial Fibrosis via Targeting Collagen Expression and the JNK Pathway in HL1 Cardiomyocytes. Int. J. Mol. Sci. 2022, 23, 9636. [Google Scholar] [CrossRef]
  92. Koski, M.K.; Anantharajan, J.; Kursula, P.; Dhavala, P.; Murthy, A.V.; Bergmann, U.; Myllyharju, J.; Wierenga, R.K. Assembly of the Elongated Collagen Prolyl 4-Hydroxylase A2β2 Heterotetramer around a Central A2 Dimer. Biochem. J. 2017, 474, 751–769. [Google Scholar] [CrossRef]
  93. Rappu, P.; Salo, A.M.; Myllyharju, J.; Heino, J. Role of Prolyl Hydroxylation in the Molecular Interactions of Collagens. Essays Biochem. 2019, 63, 325–335. [Google Scholar] [CrossRef]
  94. Luo, Y.; Xu, W.; Chen, H.; Warburton, D.; Dong, R.; Qian, B.; Selman, M.; Gauldie, J.; Kolb, M.; Shi, W. A Novel Profibrotic Mechanism Mediated by TGF-β-Stimulated Collagen Prolyl Hydroxylase Expression in Fibrotic Lung Mesenchymal Cells. J. Pathol. 2015, 236, 384. [Google Scholar] [CrossRef] [PubMed]
  95. Cao, X.; Cao, Y.; Zhao, H.; Wang, P.; Zhu, Z. Prolyl 4-Hydroxylase P4HA1 Mediates the Interplay Between Glucose Metabolism and Stemness in Pancreatic Cancer Cells. Curr. Stem Cell Res. Ther. 2023, 18, 712–719. [Google Scholar] [CrossRef] [PubMed]
  96. Gilkes, D.M.; Chaturvedi, P.; Bajpai, S.; Wong, C.C.; Wei, H.; Pitcairn, S.; Hubbi, M.E.; Wirtz, D.; Semenza, G.L. Collagen Prolyl Hydroxylases Are Essential for Breast Cancer Metastasis. Cancer Res. 2013, 73, 3285–3296. [Google Scholar] [CrossRef] [PubMed]
  97. Gjaltema, R.A.F.; Bank, R.A. Molecular Insights into Prolyl and Lysyl Hydroxylation of Fibrillar Collagens in Health and Disease. Crit. Rev. Biochem. Mol. Biol. 2017, 52, 74–95. [Google Scholar] [CrossRef] [PubMed]
  98. Terajima, M.; Taga, Y.; Cabral, W.A.; Nagasawa, M.; Sumida, N.; Hattori, S.; Marini, J.C.; Yamauchi, M. Cyclophilin B Deficiency Causes Abnormal Dentin Collagen Matrix. J. Proteome Res. 2017, 16, 2914–2923. [Google Scholar] [CrossRef] [PubMed]
  99. Marini, J.C.; Cabral, W.A.; Barnes, A.M.; Chang, W. Components of the Collagen Prolyl 3-Hydroxylation Complex Are Crucial for Normal Bone Development. Cell Cycle 2007, 6, 1675–1681. [Google Scholar] [CrossRef] [PubMed]
  100. Flaxman, H.A.; Chrysovergi, M.-A.; Han, H.; Kabir, F.; Lister, R.T.; Chang, C.-F.; Black, K.E.; Lagares, D.; Woo, C.M. Sanglifehrin A Mitigates Multi-Organ Fibrosis in Vivo by Inducing Secretion of the Collagen Chaperone Cyclophilin B. bioRxiv 2023. [Google Scholar] [CrossRef] [PubMed]
  101. Pokidysheva, E.; Boudko, S.; Vranka, J.; Zientek, K.; Maddox, K.; Moser, M.; Fässler, R.; Ware, J.; Bächinger, H.P. Biological Role of Prolyl 3-Hydroxylation in Type IV Collagen. Proc. Natl. Acad. Sci. USA 2014, 111, 161–166. [Google Scholar] [CrossRef] [PubMed]
  102. Hao, L.; Pang, K.; Pang, H.; Zhang, J.; Zhang, Z.; He, H.; Zhou, R.; Shi, Z.; Han, C. Knockdown of P3H4 Inhibits Proliferation and Invasion of Bladder Cancer. Aging 2020, 12, 2156–2168. [Google Scholar] [CrossRef]
  103. Saito, T.; Terajima, M.; Taga, Y.; Hayashi, F.; Oshima, S.; Kasamatsu, A.; Okubo, Y.; Ito, C.; Toshimori, K.; Sunohara, M.; et al. Decrease of Lysyl Hydroxylase 2 Activity Causes Abnormal Collagen Molecular Phenotypes, Defective Mineralization and Compromised Mechanical Properties of Bone. Bone 2022, 154, 116242. [Google Scholar] [CrossRef]
  104. Xu, F.; Zhang, J.; Hu, G.; Liu, L.; Liang, W. Hypoxia and TGF-Β1 Induced PLOD2 Expression Improve the Migration and Invasion of Cervical Cancer Cells by Promoting Epithelial-to-Mesenchymal Transition (EMT) and Focal Adhesion Formation. Cancer Cell Int. 2017, 17, 54. [Google Scholar] [CrossRef] [PubMed]
  105. Sato, K.; Parag-Sharma, K.; Terajima, M.; Musicant, A.M.; Murphy, R.M.; Ramsey, M.R.; Hibi, H.; Yamauchi, M.; Amelio, A.L. Lysyl Hydroxylase 2-Induced Collagen Cross-Link Switching Promotes Metastasis in Head and Neck Squamous Cell Carcinomas. Neoplasia 2021, 23, 594–606. [Google Scholar] [CrossRef] [PubMed]
  106. Lee, J.; Guo, H.; Wang, S.; Maghsoud, Y.; Vázquez-Montelongo, E.A.; Jing, Z.; Sammons, R.M.; Cho, E.J.; Ren, P.; Cisneros, G.A.; et al. Unleashing the Potential of 1,3-Diketone Analogues as Selective LH2 Inhibitors. ACS Med. Chem. Lett. 2023, 14, 1396–1403. [Google Scholar] [CrossRef] [PubMed]
  107. Baumann, S.; Hennet, T. Collagen Accumulation in Osteosarcoma Cells Lacking GLT25D1 Collagen Galactosyltransferase. J. Biol. Chem. 2016, 291, 18514–18524. [Google Scholar] [CrossRef] [PubMed]
  108. Wang, S.; He, L.; Xiao, F.; Gao, M.; Wei, H.; Yang, J.; Shu, Y.; Zhang, F.; Ye, X.; Li, P.; et al. Upregulation of GLT25D1 in Hepatic Stellate Cells Promotes Liver Fibrosis via the TGF-Β1/SMAD3 Pathway In Vivo and In Vitro. J. Clin. Transl. Hepatol. 2023, 11, 1–14. [Google Scholar] [CrossRef]
  109. Li, R.C.; Wong, M.Y.; DiChiara, A.S.; Hosseini, A.S.; Shoulders, M.D. Collagen’s Enigmatic, Highly Conserved N-Glycan Has an Essential Proteostatic Function. Proc. Natl. Acad. Sci. USA 2021, 118, e2026608118. [Google Scholar] [CrossRef]
  110. Kozlov, G.; Määttänen, P.; Thomas, D.Y.; Gehring, K. A Structural Overview of the PDI Family of Proteins. FEBS J. 2010, 277, 3924–3936. [Google Scholar] [CrossRef]
  111. Bekendam, R.H.; Flaumenhaft, R. Inhibition of Protein Disulfide Isomerase in Thrombosis. Basic. Clin. Pharmacol. Toxicol. 2016, 119, 42–48. [Google Scholar] [CrossRef] [PubMed]
  112. Flaumenhaft, R.; Furie, B.; Zwicker, J.I. Therapeutic Implications of Protein Disulfide Isomerase Inhibition in Thrombotic Disease. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 16–23. [Google Scholar] [CrossRef]
  113. DiChiara, A.S.; Taylor, R.J.; Wong, M.Y.; Doan, N.D.; Del Rosario, A.M.; Shoulders, M.D. Mapping and Exploring the Collagen-I Proteostasis Network. ACS Chem. Biol. 2016, 11, 1408–1421. [Google Scholar] [CrossRef]
  114. Paglia, G.; Minacori, M.; Meschiari, G.; Fiorini, S.; Chichiarelli, S.; Eufemi, M.; Altieri, F. Protein Disulfide Isomerase A3 (PDIA3): A Pharmacological Target in Glioblastoma? Int. J. Mol. Sci. 2023, 24, 13279. [Google Scholar] [CrossRef] [PubMed]
  115. Revert, F.; Ventura, I.; Martínez-Martínez, P.; Granero-Moltó, F.; Revert-Ros, F.; Macías, J.; Saus, J. Goodpasture Antigen-Binding Protein Is a Soluble Exportable Protein That Interacts with Type IV Collagen. J. Biol. Chem. 2008, 283, 30246. [Google Scholar] [CrossRef] [PubMed]
  116. Rasche, L.; Duell, J.; Castro, I.C.; Dubljevic, V.; Chatterjee, M.; Knop, S.; Hensel, F.; Rosenwald, A.; Einsele, H.; Topp, M.S.; et al. GRP78-Directed Immunotherapy in Relapsed or Refractory Multiple Myeloma-Results from a Phase 1 Trial with the Monoclonal Immunoglobulin M Antibody PAT-SM6. Haematologica 2015, 100, 377–384. [Google Scholar] [CrossRef] [PubMed]
  117. Elfiky, A.A.; Baghdady, A.M.; Ali, S.A.; Ahmed, M.I. GRP78 Targeting: Hitting Two Birds with a Stone. Life Sci. 2020, 260, 118317. [Google Scholar] [CrossRef] [PubMed]
  118. Kim, J.; Cho, Y.; Lee, S. Cell Surface GRP94 as a Novel Emerging Therapeutic Target for Monoclonal Antibody Cancer Therapy. Cells 2021, 10, 670. [Google Scholar] [CrossRef] [PubMed]
  119. Siekierka, J.J.; Hung, S.H.; Poe, M.; Lin, C.S.; Sigal, N.H. A Cytosolic Binding Protein for the Immunosuppressant FK506 Has Peptidyl-Prolyl Isomerase Activity but Is Distinct from Cyclophilin. Nature 1989, 341, 755–757. [Google Scholar] [CrossRef] [PubMed]
  120. Ishikawa, Y.; Vranka, J.; Wirz, J.; Nagata, K.; Bächinger, H.P. The Rough Endoplasmic Reticulum-Resident FK506-Binding Protein FKBP65 Is a Molecular Chaperone That Interacts with Collagens. J. Biol. Chem. 2008, 283, 31584–31590. [Google Scholar] [CrossRef] [PubMed]
  121. Schwarze, U.; Cundy, T.; Pyott, S.M.; Christiansen, H.E.; Hegde, M.R.; Bank, R.A.; Pals, G.; Ankala, A.; Conneely, K.; Seaver, L.; et al. Mutations in FKBP10, Which Result in Bruck Syndrome and Recessive Forms of Osteogenesis Imperfecta, Inhibit the Hydroxylation of Telopeptide Lysines in Bone Collagen. Hum. Mol. Genet. 2013, 22, 1–17. [Google Scholar] [CrossRef] [PubMed]
  122. Staab-Weijnitz, C.A.; Fernandez, I.E.; Knüppel, L.; Maul, J.; Heinzelmann, K.; Juan-Guardela, B.M.; Hennen, E.; Preissler, G.; Winter, H.; Neurohr, C.; et al. FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 2015, 192, 455–467. [Google Scholar] [CrossRef]
  123. Xie, S.; Xing, Y.; Shi, W.; Zhang, M.; Chen, M.; Fang, W.; Liu, S.; Zhang, T.; Zeng, X.; Chen, S.; et al. Cardiac Fibroblast Heat Shock Protein 47 Aggravates Cardiac Fibrosis Post Myocardial Ischemia–Reperfusion Injury by Encouraging Ubiquitin Specific Peptidase 10 Dependent Smad4 Deubiquitination. Acta Pharm. Sin. B 2022, 12, 4138–4153. [Google Scholar] [CrossRef]
  124. Qosa, H.; de Oliveira, C.H.M.C.; Cizza, G.; Lawitz, E.J.; Colletti, N.; Wetherington, J.; Charles, E.D.; Tirucherai, G.S. Pharmacokinetics, Safety, and Tolerability of BMS-986263, a Lipid Nanoparticle Containing HSP47 siRNA, in Participants with Hepatic Impairment. Clin. Transl. Sci. 2023, 16, 1791–1802. [Google Scholar] [CrossRef] [PubMed]
  125. Ma, W.; Goldberg, J. TANGO1/cTAGE5 Receptor as a Polyvalent Template for Assembly of Large COPII Coats. Proc. Natl. Acad. Sci. USA 2016, 113, 10061–10066. [Google Scholar] [CrossRef] [PubMed]
  126. Raote, I.; Ortega-Bellido, M.; Santos, A.J.; Foresti, O.; Zhang, C.; Garcia-Parajo, M.F.; Campelo, F.; Malhotra, V. TANGO1 Builds a Machine for Collagen Export by Recruiting and Spatially Organizing COPII, Tethers and Membranes. eLife 2018, 7, e32723. [Google Scholar] [CrossRef] [PubMed]
  127. Wilson, D.G.; Phamluong, K.; Li, L.; Sun, M.; Cao, T.C.; Liu, P.S.; Modrusan, Z.; Sandoval, W.N.; Rangell, L.; Carano, R.A.D.; et al. Global Defects in Collagen Secretion in a Mia3/TANGO1 Knockout Mouse. J. Cell Biol. 2011, 193, 935–951. [Google Scholar] [CrossRef] [PubMed]
  128. Santos, A.J.; Nogueira, C.; Ortega-Bellido, M.; Malhotra, V. TANGO1 and Mia2/cTAGE5 (TALI) cooperate to export bulky pre-chylomicrons/VLDLs from the endoplasmic reticulum. J. Cell Biol. 2016, 213, 343–354. [Google Scholar] [CrossRef] [PubMed]
  129. Man, J.; Zhou, W.; Zuo, S.; Zhao, X.; Wang, Q.; Ma, H.; Li, H.-Y. TANGO1 Interacts with NRTN to Promote Hepatocellular Carcinoma Progression by Regulating the PI3K/AKT/mTOR Signaling Pathway. Biochem. Pharmacol. 2023, 213, 115615. [Google Scholar] [CrossRef] [PubMed]
  130. Arnolds, O.; Stoll, R. Characterization of a Fold in TANGO1 Evolved from SH3 Domains for the Export of Bulky Cargos. Nat. Commun. 2023, 14, 2273. [Google Scholar] [CrossRef] [PubMed]
  131. Vadon-Le Goff, S.; Hulmes, D.J.S.; Moali, C. BMP-1/Tolloid-like Proteinases Synchronize Matrix Assembly with Growth Factor Activation to Promote Morphogenesis and Tissue Remodeling. Matrix Biol. 2015, 44–46, 14–23. [Google Scholar] [CrossRef] [PubMed]
  132. Katagiri, T.; Watabe, T. Bone Morphogenetic Proteins. Cold Spring Harb. Perspect. Biol. 2016, 8, a021899. [Google Scholar] [CrossRef]
  133. Grgurevic, L.; Erjavec, I.; Grgurevic, I.; Dumic-Cule, I.; Brkljacic, J.; Verbanac, D.; Matijasic, M.; Paljetak, H.C.; Novak, R.; Plecko, M.; et al. Systemic Inhibition of BMP1-3 Decreases Progression of CCl4-Induced Liver Fibrosis in Rats. Growth Factors 2017, 35, 201–215. [Google Scholar] [CrossRef]
  134. Talantikite, M.; Lécorché, P.; Beau, F.; Damour, O.; Becker-Pauly, C.; Ho, W.; Dive, V.; Vadon-Le Goff, S.; Moali, C. Inhibitors of BMP-1/Tolloid-like Proteinases: Efficacy, Selectivity and Cellular Toxicity. FEBS Open Bio 2018, 8, 2011–2021. [Google Scholar] [CrossRef]
  135. Bai, M.; Lei, J.; Wang, S.; Ding, D.; Yu, X.; Guo, Y.; Chen, S.; Du, Y.; Li, D.; Zhang, Y.; et al. BMP1 Inhibitor UK383,367 Attenuates Renal Fibrosis and Inflammation in CKD. Am. J. Physiol. Renal Physiol. 2019, 317, F1430–F1438. [Google Scholar] [CrossRef] [PubMed]
  136. Ma, H.-Y.; N’Diaye, E.-N.; Caplazi, P.; Huang, Z.; Arlantico, A.; Jeet, S.; Wong, A.; Brightbill, H.D.; Li, Q.; Wong, W.R.; et al. BMP1 Is Not Required for Lung Fibrosis in Mice. Sci. Rep. 2022, 12, 5466. [Google Scholar] [CrossRef] [PubMed]
  137. Bekhouche, M.; Colige, A. The Procollagen N-Proteinases ADAMTS2, 3 and 14 in Pathophysiology. Matrix Biol. 2015, 44–46, 46–53. [Google Scholar] [CrossRef] [PubMed]
  138. Kelwick, R.; Desanlis, I.; Wheeler, G.N.; Edwards, D.R. The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin Motifs) Family. Genome Biol. 2015, 16, 113. [Google Scholar] [CrossRef] [PubMed]
  139. Brebion, F.; Gosmini, R.; Deprez, P.; Varin, M.; Peixoto, C.; Alvey, L.; Jary, H.; Bienvenu, N.; Triballeau, N.; Blanque, R.; et al. Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. J. Med. Chem. 2021, 64, 2937–2952. [Google Scholar] [CrossRef] [PubMed]
  140. Canty, E.G.; Lu, Y.; Meadows, R.S.; Shaw, M.K.; Holmes, D.F.; Kadler, K.E. Coalignment of Plasma Membrane Channels and Protrusions (Fibripositors) Specifies the Parallelism of Tendon. J. Cell Biol. 2004, 165, 553–563. [Google Scholar] [CrossRef] [PubMed]
  141. Musiime, M.; Chang, J.; Hansen, U.; Kadler, K.E.; Zeltz, C.; Gullberg, D. Collagen Assembly at the Cell Surface: Dogmas Revisited. Cells 2021, 10, 662. [Google Scholar] [CrossRef] [PubMed]
  142. Revell, C.K.; Herrera, J.A.; Lawless, C.; Lu, Y.; Kadler, K.E.; Chang, J.; Jensen, O.E. Modeling Collagen Fibril Self-Assembly from Extracellular Medium in Embryonic Tendon. Biophys. J. 2023, 122, 3219–3237. [Google Scholar] [CrossRef]
  143. Lloyd, S.M.; He, Y. Exploring Extracellular Matrix Crosslinking as a Therapeutic Approach to Fibrosis. Cells 2024, 13, 438. [Google Scholar] [CrossRef]
  144. Eyre, D.R.; Weis, M.; Rai, J. Analyses of Lysine Aldehyde Cross-Linking in Collagen Reveal That the Mature Cross-Link Histidinohydroxylysinonorleucine Is an Artifact. J. Biol. Chem. 2019, 294, 6578–6590. [Google Scholar] [CrossRef] [PubMed]
  145. Yamauchi, M.; Taga, Y.; Terajima, M. Analyses of Lysine Aldehyde Cross-Linking in Collagen Reveal That the Mature Cross-Link Histidinohydroxylysinonorleucine Is an Artifact. J. Biol. Chem. 2019, 294, 14163. [Google Scholar] [CrossRef] [PubMed]
  146. Shetty, S.S.; Sharma, M.; Kabekkodu, S.P.; Kumar, N.A.; Satyamoorthy, K.; Radhakrishnan, R. Understanding the Molecular Mechanism Associated with Reversal of Oral Submucous Fibrosis Targeting Hydroxylysine Aldehyde-Derived Collagen Cross-Links. J. Carcinog. 2021, 20, 9. [Google Scholar] [PubMed]
  147. Rosell-García, T.; Paradela, A.; Bravo, G.; Dupont, L.; Bekhouche, M.; Colige, A.; Rodriguez-Pascual, F. Differential Cleavage of Lysyl Oxidase by the Metalloproteinases BMP1 and ADAMTS2/14 Regulates Collagen Binding through a Tyrosine Sulfate Domain. J. Biol. Chem. 2019, 294, 11087–11100. [Google Scholar] [CrossRef] [PubMed]
  148. Barry, V.; Spangler, R.; Marshall, D.; McCauley, S.; Rodriguez, H.; Oyasu, M.; Mikels, A.; Vaysberg, M.; Ghermazien, H.; Wai, C.; et al. Allosteric Inhibition of Lysyl Oxidase-like-2 Impedes the Development of a Pathologic Microenvironment. Nat. Med. 2010, 16, 1009–1017. [Google Scholar] [CrossRef] [PubMed]
  149. Raghu, G.; Brown, K.K.; Collard, H.R.; Cottin, V.; Gibson, K.F.; Kaner, R.J.; Lederer, D.J.; Martinez, F.J.; Noble, P.W.; Song, J.W.; et al. Efficacy of Simtuzumab versus Placebo in Patients with Idiopathic Pulmonary Fibrosis: A Randomised, Double-Blind, Controlled, Phase 2 Trial. Lancet Respir. Med. 2017, 5, 22–32. [Google Scholar] [CrossRef] [PubMed]
  150. Muir, A.J.; Levy, C.; Janssen, H.L.A.; Montano-Loza, A.J.; Shiffman, M.L.; Caldwell, S.; Luketic, V.; Ding, D.; Jia, C.; McColgan, B.J.; et al. Simtuzumab for Primary Sclerosing Cholangitis: Phase 2 Study Results With Insights on the Natural History of the Disease. Hepatology 2019, 69, 684–698. [Google Scholar] [CrossRef] [PubMed]
  151. Verstovsek, S.; Savona, M.R.; Mesa, R.A.; Oh, S.; Dong, H.; Thai, D.; Gotlib, J. A Phase 2 Study to Evaluate the Efficacy and Safety of Simtuzumab in Adult Subjects with Primary, Post Polycythemia Vera (PV) or Post Essential Thrombocythemia (ET) Myelofibrosis. Blood 2015, 126, 2810. [Google Scholar] [CrossRef]
  152. Harrison, S.A.; Abdelmalek, M.F.; Caldwell, S.; Shiffman, M.L.; Diehl, A.M.; Ghalib, R.; Lawitz, E.J.; Rockey, D.C.; Schall, R.A.; Jia, C.; et al. Simtuzumab Is Ineffective for Patients With Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis. Gastroenterology 2018, 155, 1140–1153. [Google Scholar] [CrossRef] [PubMed]
  153. Meissner, E.G.; McLaughlin, M.; Matthews, L.; Gharib, A.M.; Wood, B.J.; Levy, E.; Sinkus, R.; Virtaneva, K.; Sturdevant, D.; Martens, C.; et al. Simtuzumab Treatment of Advanced Liver Fibrosis in HIV and HCV-Infected Adults: Results of a 6-Month Open-Label Safety Trial. Liver Int. 2016, 36, 1783–1792. [Google Scholar] [CrossRef]
  154. Benson, A.B.; Wainberg, Z.A.; Hecht, J.R.; Vyushkov, D.; Dong, H.; Bendell, J.; Kudrik, F. A Phase II Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab or Placebo in Combination with Gemcitabine for the First-Line Treatment of Pancreatic Adenocarcinoma. Oncologist 2017, 22, 241-e15. [Google Scholar] [CrossRef] [PubMed]
  155. Hecht, J.R.; Benson, A.B.; Vyushkov, D.; Yang, Y.; Bendell, J.; Verma, U. A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Simtuzumab in Combination with FOLFIRI for the Second-Line Treatment of Metastatic KRAS Mutant Colorectal Adenocarcinoma. Oncologist 2017, 22, 243-e23. [Google Scholar] [CrossRef] [PubMed]
  156. Eraso, P.; Mazón, M.J.; Jiménez, V.; Pizarro-García, P.; Cuevas, E.P.; Majuelos-Melguizo, J.; Morillo-Bernal, J.; Cano, A.; Portillo, F. New Functions of Intracellular LOXL2: Modulation of RNA-Binding Proteins. Molecules 2023, 28, 4433. [Google Scholar] [CrossRef] [PubMed]
  157. M.D. Anderson Cancer Center. Open Label Phase 2 Single Agent Study of PAT-1251 in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF). clinicaltrials.gov, 2019. Available online: https://www.clinicaltrials.gov/search?term=NCT04054245 (accessed on 7 June 2024).
  158. Syntara. A Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients with Primary, Postpolycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis. clinicaltrials.gov, 2024. Available online: https://www.clinicaltrials.gov/search?term=NCT04676529 (accessed on 7 June 2024).
  159. Vachhani, P.; Baskar, J.; Charlton, B.; Cheung, S.; Jarolimek, W.; Lee, S.-E.; Tan, P.; Watson, A.M.; Wu, S.-J. PXS5505-MF-101: A Phase 1/2a Study to Evaluate Safety, Pharmacokinetics and Pharmacodynamics of Pxs-5505 in Patients with Primary, Post-Polycythemia Vera or Post-Essential Thrombocythemia Myelofibrosis. Blood 2023, 142, 625. [Google Scholar] [CrossRef]
  160. Badri, N. A Phase 1b/2 Trial of PXS-5505 Combined with First Line Atezolizumab Plus Bevacizumab for Treating Patients with Unresectable Hepatocellular Carcinoma. clinicaltrials.gov, 2023. Available online: https://www.clinicaltrials.gov/search?term=NCT05109052 (accessed on 7 June 2024).
  161. Vanacore, R.; Friedman, D.; Ham, A.; Sundaramoorthy, M.; Hudson, B. Identification of S-Hydroxylysyl-Methionine as the Covalent Cross-Link of the Noncollagenous (NC1) Hexamer of the A1α1α2 Collagen IV Network. J. Biol. Chem. 2005, 280, 29300–29310. [Google Scholar] [CrossRef] [PubMed]
  162. Cheng, G.; Shi, R. Mammalian Peroxidasin (PXDN): From Physiology to Pathology. Free Radic. Biol. Med. 2022, 182, 100–107. [Google Scholar] [CrossRef] [PubMed]
  163. Nelson, R.E.; Fessler, L.I.; Takagi, Y.; Blumberg, B.; Keene, D.R.; Olson, P.F.; Parker, C.G.; Fessler, J.H. Peroxidasin: A Novel Enzyme-matrix Protein of Drosophila Development. EMBO J. 1994, 13, 3438–3447. [Google Scholar] [CrossRef] [PubMed]
  164. Bhave, G.; Cummings, C.F.; Vanacore, R.M.; Kumagai-Cresse, C.; Ero-Tolliver, I.A.; Rafi, M.; Kang, J.-S.; Pedchenko, V.P.; Fessler, L.I.; Fessler, J.H.; et al. Peroxidasin Forms Sulfilimine Chemical Bonds Using Hypohalous Acids In Tissue Genesis. Nat. Chem. Biol. 2012, 8, 784–790. [Google Scholar] [CrossRef] [PubMed]
  165. Colon, S.; Luan, H.; Liu, Y.; Meyer, C.; Gewin, L.; Bhave, G. Peroxidasin and Eosinophil Peroxidase, but Not Myeloperoxidase, Contribute to Renal Fibrosis in the Murine Unilateral Ureteral Obstruction Model. Am. J. Physiol. Renal Physiol. 2019, 316, F360–F371. [Google Scholar] [CrossRef]
  166. Paumann-Page, M.; Obinger, C.; Winterbourn, C.C.; Furtmüller, P.G. Peroxidasin Inhibition by Phloroglucinol and Other Peroxidase Inhibitors. Antioxidants 2024, 13, 23. [Google Scholar] [CrossRef]
  167. Kumar, V.A.; Taylor, N.L.; Jalan, A.A.; Hwang, L.K.; Wang, B.K.; Hartgerink, J.D. A Nanostructured Synthetic Collagen Mimic for Hemostasis. Biomacromolecules 2014, 15, 1484–1490. [Google Scholar] [CrossRef] [PubMed]
  168. Maquart, F.X.; Siméon, A.; Pasco, S.; Monboisse, J.C. Regulation of cell activity by the extracellular matrix: The concept of matrikines. J. Soc. Biol. 1999, 193, 423–428. [Google Scholar] [CrossRef] [PubMed]
  169. Davis, G.E.; Bayless, K.J.; Davis, M.J.; Meininger, G.A. Regulation of Tissue Injury Responses by the Exposure of Matricryptic Sites within Extracellular Matrix Molecules. Am. J. Pathol. 2000, 156, 1489–1498. [Google Scholar] [CrossRef] [PubMed]
  170. Lindsey, M.L.; Iyer, R.P.; Zamilpa, R.; Yabluchanskiy, A.; DeLeon-Pennell, K.Y.; Hall, M.E.; Kaplan, A.; Zouein, F.A.; Bratton, D.; Flynn, E.R.; et al. A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis. J. Am. Coll. Cardiol. 2015, 66, 1364–1374. [Google Scholar] [CrossRef] [PubMed]
  171. Grilo, G.A.; Cakir, S.N.; Shaver, P.R.; Iyer, R.P.; Whitehead, K.; McClung, J.M.; Vahdati, A.; de Castro Brás, L.E. Collagen Matricryptin Promotes Cardiac Function by Mediating Scar Formation. Life Sci. 2023, 321, 121598. [Google Scholar] [CrossRef] [PubMed]
  172. Pozzo, C.F.S.D.; Sielski, M.S.; de Campos Vidal, B.; Werneck, C.C.; Vicente, C.P. A Collagen I Derived Matricryptin Increases Aorta Vascular Wall Remodeling after Induced Thrombosis in Mouse. Thromb. Res. 2022, 209, 59–68. [Google Scholar] [CrossRef] [PubMed]
  173. Gauci, S.J.; Golub, S.B.; Tatarczuch, L.; Lee, E.; Chan, D.; Walsh, N.C.; Little, C.B.; Stanton, H.; Lokmic, Z.; Sims, N.A.; et al. Disrupted Type II Collagenolysis Impairs Angiogenesis, Delays Endochondral Ossification and Initiates Aberrant Ossification in Mouse Limbs. Matrix Biol. 2019, 83, 77–96. [Google Scholar] [CrossRef] [PubMed]
  174. Zhu, L.; Guo, Z.; Zhang, J.; Yang, Y.; Liu, C.; Zhang, L.; Gu, Z.; Li, Y.; Ding, Z.; Shi, G. Recombinant Human Arresten and Canstatin Inhibit Angiogenic Behaviors of HUVECs via Inhibiting the PI3K/Akt Signaling Pathway. Int. J. Mol. Sci. 2022, 23, 8995. [Google Scholar] [CrossRef] [PubMed]
  175. Kamphaus, G.D.; Colorado, P.C.; Panka, D.J.; Hopfer, H.; Ramchandran, R.; Torre, A.; Maeshima, Y.; Mier, J.W.; Sukhatme, V.P.; Kalluri, R. Canstatin, a Novel Matrix-Derived Inhibitor of Angiogenesis and Tumor Growth. J. Biol. Chem. 2000, 275, 1209–1215. [Google Scholar] [CrossRef]
  176. Colorado, P.C.; Torre, A.; Kamphaus, G.; Maeshima, Y.; Hopfer, H.; Takahashi, K.; Volk, R.; Zamborsky, E.D.; Herman, S.; Sarkar, P.K.; et al. Anti-Angiogenic Cues from Vascular Basement Membrane Collagen. Cancer Res. 2000, 60, 2520–2526. [Google Scholar]
  177. Aikio, M.; Alahuhta, I.; Nurmenniemi, S.; Suojanen, J.; Palovuori, R.; Teppo, S.; Sorsa, T.; López-Otín, C.; Pihlajaniemi, T.; Salo, T.; et al. Arresten, a Collagen-Derived Angiogenesis Inhibitor, Suppresses Invasion of Squamous Cell Carcinoma. PLoS ONE 2012, 7, e51044. [Google Scholar] [CrossRef]
  178. Sugiyama, A.; Shimizu, Y.; Okada, M.; Otani, K.; Yamawaki, H. Preventive Effect of Canstatin against Ventricular Arrhythmia Induced by Ischemia/Reperfusion Injury: A Pilot Study. Int. J. Mol. Sci. 2021, 22, 1004. [Google Scholar] [CrossRef] [PubMed]
  179. Sugiyama, A.; Kaisho, M.; Okada, M.; Otani, K.; Yamawaki, H. Decreased Expression of Canstatin in Rat Model of Monocrotaline-Induced Pulmonary Arterial Hypertension: Protective Effect of Canstatin on Right Ventricular Remodeling. Int. J. Mol. Sci. 2020, 21, 6797. [Google Scholar] [CrossRef] [PubMed]
  180. Sudhakar, A.; Sugimoto, H.; Yang, C.; Lively, J.; Zeisberg, M.; Kalluri, R. Human Tumstatin and Human Endostatin Exhibit Distinct Antiangiogenic Activities Mediated by Alpha v Beta 3 and Alpha 5 Beta 1 Integrins. Proc. Natl. Acad. Sci. USA 2003, 100, 4766–4771. [Google Scholar] [CrossRef] [PubMed]
  181. Maeshima, Y.; Yerramalla, U.L.; Dhanabal, M.; Holthaus, K.A.; Barbashov, S.; Kharbanda, S.; Reimer, C.; Manfredi, M.; Dickerson, W.M.; Kalluri, R. Extracellular Matrix-Derived Peptide Binds to Alpha(v)Beta(3) Integrin and Inhibits Angiogenesis. J. Biol. Chem. 2001, 276, 31959–31968. [Google Scholar] [CrossRef]
  182. Liu, F.; Wang, F.; Dong, X.; Xiu, P.; Sun, P.; Li, Z.; Shi, X.; Zhong, J. T7 Peptide Cytotoxicity in Human Hepatocellular Carcinoma Cells Is Mediated by Suppression of Autophagy. Int. J. Mol. Med. 2019, 44, 523–534. [Google Scholar] [CrossRef]
  183. Riaz, M.K.; Zhang, X.; Wong, K.H.; Chen, H.; Liu, Q.; Chen, X.; Zhang, G.; Lu, A.; Yang, Z. Pulmonary Delivery of Transferrin Receptors Targeting Peptide Surface-Functionalized Liposomes Augments the Chemotherapeutic Effect of Quercetin in Lung Cancer Therapy. Int. J. Nanomed. 2019, 14, 2879–2902. [Google Scholar] [CrossRef] [PubMed]
  184. Zhu, C.; Zuo, Z.; Xu, C.; Ji, M.; He, J.; Li, J. Tumstatin (69–88) Alleviates Heart Failure via Attenuating Oxidative Stress in Rats with Myocardial Infarction. Heliyon 2022, 8, e10582. [Google Scholar] [CrossRef]
  185. Yasuda, J.; Okada, M.; Yamawaki, H. T3 Peptide, an Active Fragment of Tumstatin, Inhibits H2O2-Induced Apoptosis in H9c2 Cardiomyoblasts. Eur. J. Pharmacol. 2017, 807, 64–70. [Google Scholar] [CrossRef]
  186. Ocugen. A Phase 1 Study to Assess the Safety and Efficacy Of OCU200 For Center-Involved Diabetic Macular Edema. clinicaltrials.gov, 2023. Available online: https://www.clinicaltrials.gov/search?term=NCT05802329 (accessed on 7 June 2024).
  187. Upadhyay, A.K.; Arumugham, R.; Naha, P.; Singh, D. OCU200 (Transferrin-Tumstatin Fusion Protein): A Potential Therapeutic for DME, DR, and Wet-AMD. Investig. Ophthalmol. Vis. Sci. 2021, 62, 992. [Google Scholar]
  188. Petitclerc, E.; Boutaud, A.; Prestayko, A.; Xu, J.; Sado, Y.; Ninomiya, Y.; Sarras, M.P.; Hudson, B.G.; Brooks, P.C. New Functions for Non-Collagenous Domains of Human Collagen Type IV. Novel Integrin Ligands Inhibiting Angiogenesis and Tumor Growth in Vivo. J. Biol. Chem. 2000, 275, 8051–8061. [Google Scholar] [CrossRef] [PubMed]
  189. Karagiannis, E.D.; Popel, A.S. A Systematic Methodology for Proteome-Wide Identification of Peptides Inhibiting the Proliferation and Migration of Endothelial Cells. Proc. Natl. Acad. Sci. USA 2008, 105, 13775–13780. [Google Scholar] [CrossRef] [PubMed]
  190. Brassart-Pasco, S.; Sénéchal, K.; Thevenard, J.; Ramont, L.; Devy, J.; Di Stefano, L.; Dupont-Deshorgue, A.; Brézillon, S.; Feru, J.; Jazeron, J.-F.; et al. Tetrastatin, the NC1 Domain of the A4(IV) Collagen Chain: A Novel Potent Anti-Tumor Matrikine. PLoS ONE 2012, 7, e29587. [Google Scholar] [CrossRef] [PubMed]
  191. Lambert, E.; Fuselier, E.; Ramont, L.; Brassart, B.; Dukic, S.; Oudart, J.-B.; Dupont-Deshorgue, A.; Sellier, C.; Machado, C.; Dauchez, M.; et al. Conformation-Dependent Binding of a Tetrastatin Peptide to Avβ3 Integrin Decreases Melanoma Progression through FAK/PI3K/Akt Pathway Inhibition. Sci. Rep. 2018, 8, 9837. [Google Scholar] [CrossRef] [PubMed]
  192. Vautrin-Glabik, A.; Devy, J.; Bour, C.; Baud, S.; Choulier, L.; Hoarau, A.; Dupont-Deshorgue, A.; Sellier, C.; Brassart, B.; Oudart, J.-B.; et al. Angiogenesis Inhibition by a Short 13 Amino Acid Peptide Sequence of Tetrastatin, the A4(IV) NC1 Domain of Collagen IV. Front. Cell Dev. Biol. 2020, 8, 775. [Google Scholar] [CrossRef] [PubMed]
  193. Koskimaki, J.E.; Karagiannis, E.D.; Tang, B.C.; Hammers, H.; Watkins, D.N.; Pili, R.; Popel, A.S. Pentastatin-1, a Collagen IV Derived 20-Mer Peptide, Suppresses Tumor Growth in a Small Cell Lung Cancer Xenograft Model. BMC Cancer 2010, 10, 29. [Google Scholar] [CrossRef] [PubMed]
  194. Mutgan, A.C.; Jandl, K.; Radic, N.; Valzano, F.; Kolb, D.; Hoffmann, J.; Foris, V.; Wilhelm, J.; Boehm, P.M.; Hoetzenecker, K.; et al. Pentastatin, a Matrikine of the Collagen IVα5, Is a Novel Endogenous Mediator of Pulmonary Endothelial Dysfunction. Am. J. Physiol. Cell Physiol. 2023, 325, C1294–C1312. [Google Scholar] [CrossRef] [PubMed]
  195. Weckmann, M.; Moir, L.M.; Heckman, C.A.; Black, J.L.; Oliver, B.G.; Burgess, J.K. Lamstatin-a Novel Inhibitor of Lymphangiogenesis Derived from Collagen IV. J. Cell. Mol. Med. 2012, 16, 3062–3073. [Google Scholar] [CrossRef] [PubMed]
  196. Mundel, T.M.; Yliniemi, A.-M.; Maeshima, Y.; Sugimoto, H.; Kieran, M.; Kalluri, R. Type IV Collagen Alpha6 Chain-Derived Noncollagenous Domain 1 (Alpha6(IV)NC1) Inhibits Angiogenesis and Tumor Growth. Int. J. Cancer 2008, 122, 1738–1744. [Google Scholar] [CrossRef]
  197. Gunda, V.; Verma, R.K.; Sudhakar, Y.A. Inhibition of Elastin Peptide-Mediated Angiogenic Signaling Mechanism(s) in Choroidal Endothelial Cells by the A6(IV)NC1 Collagen Fragment. Investig. Ophthalmol. Vis. Sci. 2013, 54, 7828–7835. [Google Scholar] [CrossRef]
  198. Xu, R.; Yao, Z.Y.; Xin, L.; Zhang, Q.; Li, T.P.; Gan, R.B. NC1 Domain of Human Type VIII Collagen (Alpha 1) Inhibits Bovine Aortic Endothelial Cell Proliferation and Causes Cell Apoptosis. Biochem. Biophys. Res. Commun. 2001, 289, 264–268. [Google Scholar] [CrossRef] [PubMed]
  199. Shen, Z.; Yao, C.; Wang, Z.; Yue, L.; Fang, Z.; Yao, H.; Lin, F.; Zhao, H.; Sun, Y.-J.; Bian, X.-W.; et al. Vastatin, an Endogenous Antiangiogenesis Polypeptide That Is Lost in Hepatocellular Carcinoma, Effectively Inhibits Tumor Metastasis. Mol. Ther. 2016, 24, 1358–1368. [Google Scholar] [CrossRef] [PubMed]
  200. Li, Y.; Li, J.; Woo, Y.M.; Shen, Z.; Yao, H.; Cai, Y.; Lin, M.C.-M.; Poon, W.S. Enhanced Expression of Vastatin Inhibits Angiogenesis and Prolongs Survival in Murine Orthotopic Glioblastoma Model. BMC Cancer 2017, 17, 126. [Google Scholar] [CrossRef] [PubMed]
  201. O’Reilly, M.S.; Boehm, T.; Shing, Y.; Fukai, N.; Vasios, G.; Lane, W.S.; Flynn, E.; Birkhead, J.R.; Olsen, B.R.; Folkman, J. Endostatin: An Endogenous Inhibitor of Angiogenesis and Tumor Growth. Cell 1997, 88, 277–285. [Google Scholar] [CrossRef] [PubMed]
  202. Kim, Y.-M.; Hwang, S.; Kim, Y.-M.; Pyun, B.-J.; Kim, T.-Y.; Lee, S.-T.; Gho, Y.S.; Kwon, Y.-G. Endostatin Blocks Vascular Endothelial Growth Factor-Mediated Signaling via Direct Interaction with KDR/Flk-1. J. Biol. Chem. 2002, 277, 27872–27879. [Google Scholar] [CrossRef] [PubMed]
  203. Rehn, M.; Veikkola, T.; Kukk-Valdre, E.; Nakamura, H.; Ilmonen, M.; Lombardo, C.; Pihlajaniemi, T.; Alitalo, K.; Vuori, K. Interaction of Endostatin with Integrins Implicated in Angiogenesis. Proc. Natl. Acad. Sci. USA 2001, 98, 1024–1029. [Google Scholar] [CrossRef] [PubMed]
  204. Shi, H.; Huang, Y.; Zhou, H.; Song, X.; Yuan, S.; Fu, Y.; Luo, Y. Nucleolin Is a Receptor That Mediates Antiangiogenic and Antitumor Activity of Endostatin. Blood 2007, 110, 2899–2906. [Google Scholar] [CrossRef] [PubMed]
  205. Tong, Y.; Zhong, K.; Tian, H.; Gao, X.; Xu, X.; Yin, X.; Yao, W. Characterization of a monoPEG20000-Endostar. Int. J. Biol. Macromol. 2010, 46, 331–336. [Google Scholar] [CrossRef] [PubMed]
  206. Guo, L.; Hua, L.; Hu, B.; Wang, J. Pre-Clinical Efficacy and Safety Pharmacology of PEGylated Recombinant Human Endostatin. Curr. Mol. Med. 2024, 24, 389–396. [Google Scholar] [CrossRef]
  207. Chen, Y.; Du, Y.; Li, P.; Wu, F.; Fu, Y.; Li, Z.; Luo, Y. Phase I Trial of M2ES, a Novel Polyethylene Glycosylated Recombinant Human Endostatin, plus Gemcitabine in Advanced Pancreatic Cancer. Mol. Clin. Oncol. 2014, 2, 586–590. [Google Scholar] [CrossRef]
  208. Cattaneo, M.G.; Pola, S.; Francescato, P.; Chillemi, F.; Vicentini, L.M. Human Endostatin-Derived Synthetic Peptides Possess Potent Antiangiogenic Properties in Vitro and in Vivo. Exp. Cell Res. 2003, 283, 230–236. [Google Scholar] [CrossRef] [PubMed]
  209. Wickström, S.A.; Alitalo, K.; Keski-Oja, J. An Endostatin-Derived Peptide Interacts with Integrins and Regulates Actin Cytoskeleton and Migration of Endothelial Cells. J. Biol. Chem. 2004, 279, 20178–20185. [Google Scholar] [CrossRef] [PubMed]
  210. Xu, H.-M.; Yin, R.; Chen, L.; Siraj, S.; Huang, X.; Wang, M.; Fang, H.; Wang, Y. An RGD-Modified Endostatin-Derived Synthetic Peptide Shows Antitumor Activity in Vivo. Bioconjug. Chem. 2008, 19, 1980–1986. [Google Scholar] [CrossRef]
  211. Yamaguchi, Y.; Takihara, T.; Chambers, R.A.; Veraldi, K.L.; Larregina, A.T.; Feghali-Bostwick, C.A. A Peptide Derived from Endostatin Ameliorates Organ Fibrosis. Sci. Transl. Med. 2012, 4, 136ra71. [Google Scholar] [CrossRef] [PubMed]
  212. Mlakar, L.; Garrett, S.M.; Watanabe, T.; Sanderson, M.; Nishimoto, T.; Heywood, J.; Helke, K.L.; Pilewski, J.M.; Herzog, E.L.; Feghali-Bostwick, C. Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants. Biomedicines 2022, 10, 2861. [Google Scholar] [CrossRef] [PubMed]
  213. Martínez-Nieto, G.; Heljasvaara, R.; Heikkinen, A.; Kaski, H.-K.; Devarajan, R.; Rinne, O.; Henriksson, C.; Thomson, E.; von Hertzen, C.; Miinalainen, I.; et al. Deletion of Col15a1 Modulates the Tumour Extracellular Matrix and Leads to Increased Tumour Growth in the MMTV-PyMT Mouse Mammary Carcinoma Model. Int. J. Mol. Sci. 2021, 22, 9978. [Google Scholar] [CrossRef] [PubMed]
  214. Ramchandran, R.; Dhanabal, M.; Volk, R.; Waterman, M.J.; Segal, M.; Lu, H.; Knebelmann, B.; Sukhatme, V.P. Antiangiogenic Activity of Restin, NC10 Domain of Human Collagen XV: Comparison to Endostatin. Biochem. Biophys. Res. Commun. 1999, 255, 735–739. [Google Scholar] [CrossRef] [PubMed]
  215. Mutolo, M.J.; Morris, K.J.; Leir, S.-H.; Caffrey, T.C.; Lewandowska, M.A.; Hollingsworth, M.A.; Harris, A. Tumor Suppression by Collagen XV Is Independent of the Restin Domain. Matrix Biol. 2012, 31, 285–289. [Google Scholar] [CrossRef] [PubMed]
  216. Ramont, L.; Brassart-Pasco, S.; Thevenard, J.; Deshorgue, A.; Venteo, L.; Laronze, J.Y.; Pluot, M.; Monboisse, J.-C.; Maquart, F.-X. The NC1 Domain of Type XIX Collagen Inhibits in Vivo Melanoma Growth. Mol. Cancer Ther. 2007, 6, 506–514. [Google Scholar] [CrossRef]
  217. Oudart, J.-B.; Brassart-Pasco, S.; Vautrin, A.; Sellier, C.; Machado, C.; Dupont-Deshorgue, A.; Brassart, B.; Baud, S.; Dauchez, M.; Monboisse, J.-C.; et al. Plasmin Releases the Anti-Tumor Peptide from the NC1 Domain of Collagen XIX. Oncotarget 2015, 6, 3656–3668. [Google Scholar] [CrossRef]
  218. Oudart, J.-B.; Villemin, M.; Brassart, B.; Sellier, C.; Terryn, C.; Dupont-Deshorgue, A.; Monboisse, J.C.; Maquart, F.-X.; Ramont, L.; Brassart-Pasco, S. F4, a Collagen XIX-Derived Peptide, Inhibits Tumor Angiogenesis through Avβ3 and A5β1 Integrin Interaction. Cell Adh. Migr. 2021, 15, 215–223. [Google Scholar] [CrossRef]
  219. Guide, S.V.; Gonzalez, M.E.; Bağcı, I.S.; Agostini, B.; Chen, H.; Feeney, G.; Steimer, M.; Kapadia, B.; Sridhar, K.; Quesada Sanchez, L.; et al. Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. N. Engl. J. Med. 2022, 387, 2211–2219. [Google Scholar] [CrossRef] [PubMed]
  220. Tovar Vetencourt, A.; Sayed-Ahmed, I.; Gomez, J.; Chen, H.; Agostini, B.; Carroll, K.; Parry, T.; Krishnan, S.; Sabater, A.L. Ocular Gene Therapy in a Patient with Dystrophic Epidermolysis Bullosa. N. Engl. J. Med. 2024, 390, 530–535. [Google Scholar] [CrossRef]
  221. Abeona Therapeutics, Inc. VIITAL: A Phase 3 Study of EB-101 for the Treatment of Recessive Dystrophic Epidermolysis Bullosa (RDEB). clinicaltrials.gov, 2022. Available online: https://www.clinicaltrials.gov/search?term=NCT04227106 (accessed on 7 June 2024).
  222. Siprashvili, Z.; Nguyen, N.T.; Gorell, E.S.; Loutit, K.; Khuu, P.; Furukawa, L.K.; Lorenz, H.P.; Leung, T.H.; Keene, D.R.; Rieger, K.E.; et al. Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa. JAMA 2016, 316, 1808–1817. [Google Scholar] [CrossRef] [PubMed]
  223. So, J.Y.; Nazaroff, J.; Iwummadu, C.V.; Harris, N.; Gorell, E.S.; Fulchand, S.; Bailey, I.; McCarthy, D.; Siprashvili, Z.; Marinkovich, M.P.; et al. Long-Term Safety and Efficacy of Gene-Corrected Autologous Keratinocyte Grafts for Recessive Dystrophic Epidermolysis Bullosa. Orphanet. J. Rare Dis. 2022, 17, 377. [Google Scholar] [CrossRef] [PubMed]
  224. Takashima, S.; Shinkuma, S.; Fujita, Y.; Nomura, T.; Ujiie, H.; Natsuga, K.; Iwata, H.; Nakamura, H.; Vorobyev, A.; Abe, R.; et al. Efficient Gene Reframing Therapy for Recessive Dystrophic Epidermolysis Bullosa with CRISPR/Cas9. J. Investig. Dermatol. 2019, 139, 1711–1721.e4. [Google Scholar] [CrossRef] [PubMed]
  225. Bonafont, J.; Mencía, Á.; García, M.; Torres, R.; Rodríguez, S.; Carretero, M.; Chacón-Solano, E.; Modamio-Høybjør, S.; Marinas, L.; León, C.; et al. Clinically Relevant Correction of Recessive Dystrophic Epidermolysis Bullosa by Dual sgRNA CRISPR/Cas9-Mediated Gene Editing. Mol. Ther. 2019, 27, 986–998. [Google Scholar] [CrossRef] [PubMed]
  226. Anzalone, A.V.; Randolph, P.B.; Davis, J.R.; Sousa, A.A.; Koblan, L.W.; Levy, J.M.; Chen, P.J.; Wilson, C.; Newby, G.A.; Raguram, A.; et al. Search-and-Replace Genome Editing without Double-Strand Breaks or Donor DNA. Nature 2019, 576, 149–157. [Google Scholar] [CrossRef] [PubMed]
  227. Hong, S.-A.; Kim, S.-E.; Lee, A.-Y.; Hwang, G.-H.; Kim, J.H.; Iwata, H.; Kim, S.-C.; Bae, S.; Lee, S.E. Therapeutic Base Editing and Prime Editing of COL7A1 Mutations in Recessive Dystrophic Epidermolysis Bullosa. Mol. Ther. 2022, 30, 2664–2679. [Google Scholar] [CrossRef]
  228. Ablinger, M.; Lettner, T.; Friedl, N.; Potocki, H.; Palmetzhofer, T.; Koller, U.; Illmer, J.; Liemberger, B.; Hainzl, S.; Klausegger, A.; et al. Personalized Development of Antisense Oligonucleotides for Exon Skipping Restores Type XVII Collagen Expression in Junctional Epidermolysis Bullosa. Int. J. Mol. Sci. 2021, 22, 3326. [Google Scholar] [CrossRef]
  229. Holostem Terapie Avanzate s.r.l. Prospective, Open-Label, Uncontrolled Clinical Trial to Assess the Safety and Efficacy of Autologous Cultured Epidermal Grafts Containing Epidermal Stem Cells Genetically Modified With a Gamma-Retroviral (Rv) Vector Carrying COL17A1 cDNA for Restoration of Epidermis in Patients With Junctional Epidermolysis Bullosa. clinicaltrials.gov, 2022. Available online: https://www.clinicaltrials.gov/search?term=NCT03490331 (accessed on 7 June 2024).
  230. Petković, I.; Bischof, J.; Kocher, T.; March, O.P.; Liemberger, B.; Hainzl, S.; Strunk, D.; Raninger, A.M.; Binder, H.-M.; Reichelt, J.; et al. COL17A1 Editing via Homology-Directed Repair in Junctional Epidermolysis Bullosa. Front. Med. 2022, 9, 976604. [Google Scholar] [CrossRef] [PubMed]
  231. Bischof, J.; March, O.P.; Liemberger, B.; Haas, S.A.; Hainzl, S.; Petković, I.; Leb-Reichl, V.; Illmer, J.; Korotchenko, E.; Klausegger, A.; et al. Paired Nicking-Mediated COL17A1 Reframing for Junctional Epidermolysis Bullosa. Mol. Ther. 2022, 30, 2680–2692. [Google Scholar] [CrossRef] [PubMed]
  232. Klermund, J.; Rhiel, M.; Kocher, T.; Chmielewski, K.O.; Bischof, J.; Andrieux, G.; El Gaz, M.; Hainzl, S.; Boerries, M.; Cornu, T.I.; et al. On- and off-Target Effects of Paired CRISPR-Cas Nickase in Primary Human Cells. Mol. Ther. 2024, 32, 1298–1310. [Google Scholar] [CrossRef] [PubMed]
  233. Yang, Y.-S.; Sato, T.; Chaugule, S.; Ma, H.; Xie, J.; Gao, G.; Shim, J.-H. AAV-Based Gene Editing of Type 1 Collagen Mutation to Treat Osteogenesis Imperfecta. Mol. Ther. Nucleic Acids 2024, 35, 102111. [Google Scholar] [CrossRef]
  234. Chen, Y.; Yang, S.; Tavormina, J.; Tampe, D.; Zeisberg, M.; Wang, H.; Mahadevan, K.K.; Wu, C.-J.; Sugimoto, H.; Chang, C.-C.; et al. Oncogenic Collagen I Homotrimers from Cancer Cells Bind to A3β1 Integrin and Impact Tumor Microbiome and Immunity to Promote Pancreatic Cancer. Cancer Cell 2022, 40, 818–834.e9. [Google Scholar] [CrossRef]
Figure 1. Phylogeny of collagen. Collagen IV is the earliest form of collagen and is normally associated with epithelial differentiation. Collagen I emerged in more advanced organisms and serves as a key component of the mesenchymal extracellular matrix. This illustration is inspired by the findings, schemes, and conclusions of Billy G. Hudson’s laboratory [12].
Figure 1. Phylogeny of collagen. Collagen IV is the earliest form of collagen and is normally associated with epithelial differentiation. Collagen I emerged in more advanced organisms and serves as a key component of the mesenchymal extracellular matrix. This illustration is inspired by the findings, schemes, and conclusions of Billy G. Hudson’s laboratory [12].
Ijms 25 06523 g001
Figure 2. Direct and indirect targeting of collagen. Schematic representation of relevant cellular processes and drugs targeting collagen expression, cleavage, assembly, and degradation in the extracellular matrix. The different targetable processes are indicated with cursive bold lettering, and the drugs listed below with the corresponding target in parentheses. In red are the drugs assayed in clinical trials registered in ClinicalTrials.org. A question mark (?) denotes that a not fully demonstrated drug target.
Figure 2. Direct and indirect targeting of collagen. Schematic representation of relevant cellular processes and drugs targeting collagen expression, cleavage, assembly, and degradation in the extracellular matrix. The different targetable processes are indicated with cursive bold lettering, and the drugs listed below with the corresponding target in parentheses. In red are the drugs assayed in clinical trials registered in ClinicalTrials.org. A question mark (?) denotes that a not fully demonstrated drug target.
Ijms 25 06523 g002
Table 1. Human collagens: types, protomeric combinations, and dysfunctional phenotypes described in OMIM. Inspired by a table of Sylvie Ricard-Blum [1]. a In red: proteoglycans (contain glycosaminoglycans). b Non-pathological alternative splicing variants. In red: primary autoantigen in autoimmune diseases. c A pseudogene in humans with two variants is denoted with italics. d It has been also described as α1(XXIX). e α1(II) has been also described as α3(XI). Chains from different collagen types are highlighted. Question marks (?) are used to denote triple helical combinations not fully characterized or phenotypes whose relationship with the indicated collagen chains is not fully demonstrated.
Table 1. Human collagens: types, protomeric combinations, and dysfunctional phenotypes described in OMIM. Inspired by a table of Sylvie Ricard-Blum [1]. a In red: proteoglycans (contain glycosaminoglycans). b Non-pathological alternative splicing variants. In red: primary autoantigen in autoimmune diseases. c A pseudogene in humans with two variants is denoted with italics. d It has been also described as α1(XXIX). e α1(II) has been also described as α3(XI). Chains from different collagen types are highlighted. Question marks (?) are used to denote triple helical combinations not fully characterized or phenotypes whose relationship with the indicated collagen chains is not fully demonstrated.
OrganizationType (+GAG) aChains (with alt. Splicing Isoforms; Autoantigen) b Triple Helical CombinationsPhenotype of Human Mutations (Affected Chain)
Basement membrane networkIVα1(IV)  α2(IV)  α3(IV)
α4(IV)  α5(IV)  α6(IV)
[α1(IV)]2 α2(IV)Angiopathies, nephropathy (α1, α2).
Kidney disease, hematuria, loss hearing, eye abnormalities (α3, α4, α5).
Deafness (α6)?.
α3(IV) α4(IV) α5(IV)
[α5(IV)]2 α6(IV)
Basketweave like networkVIα1(VI)  α2(VI)  α3(VI)
α4(VI) c  α5(VI) d  α6(IV)
α1(VI) α2(VI) α3(VI)Muscular dystrophy, myopathy (α1, α2, α3).
Involuntary movements, dystonia (α3).
Chronic neuropathic itch (α5)?
α1(VI) α2(VI) α5(VI) ?
α1(VI) α2(VI) α6(VI) ?
Hexagonal networksVIIIα1(VIII)  α2(VIII)[α1(VIII)]2  α2(VIII)Corneal dystrophy (α2).
α1(VIII)  [α2(VIII)]2
[α1(VIII)]3
[α2(VIII)]3
Xα1(X)[α1(X)]3Chondrodysplasia.
FibrillarIα1(I)  α2(I)[α1(I)]2   α2(I)Aberrant osteogenesis, osteoporosis, overly flexible joints, stretchy-fragile skin (α1, α2).
[α1(I)]3   
IIα1(II)[α1(II)]3   Hipochondrogenosis, spondyloepiphyseal dysplasia, retinal detachment.
IIIα1(III)[α1(III)]3   Joint laxity and stretchy-fragile skin, vascular problems and aortic dissection.
Vα1(V)  α2(V)  α3(V)[α1(V)]2   α2(V)Corneal problems, fibromuscular dysplasia, skin hyperextensibility, dystrophic scarring, and joint hypermobility (α1, α2).
[α1(V)]3
α1(XI) α1(V) α1(II) e
XIα1(XI)  α2(XI)α1(XI) α2(XI)  α1(II) eOphthalmologic, deafness, skeletal abnormalities, fibrochondrogenesis (α1, α2).
α1(XI) α1(V)  α1(II) e
XXIVα1(XXIV)[α1(XXIV)]3
XXVIIα1(XXVII)[α1(XXVII)]3Short stature, bilateral congenital hip dislocation, radial head dislocation, carpal coalition, scoliosis, dysmorphic face.
Fibrillar-associated collagens with interrupted triple helices (FACIT)IXα1(IX) α2(IX) α3(IX)α1(IX) α2(IX) α3(IX)Epiphyseal dysplasia, arthro-ophthalmodystrophy (α1, α2, α3).
XIIα1(XII)[α1(XII)]3Muscular dystrophy, myopathy.
XIVα1(XIV)[α1(XIV)]3Punctate abnormal thickening of the stratum corneum of the palms and soles?
XVIα1(XVI)[α1(XVI)]3
XIXα1(XIX)[α1(XIX)]3
XXα1(XX)[α1(XX)]3Striate abnormal thickening of the stratum corneum of the palms and soles?
XXIα1(XXI)[α1(XXI)]3
XXIIα1(XXII)[α1(XXII)]3
Anchoring
fibrils
VIIα1(VII)[α1(VII)]3Cutaneous and mucosal fragility resulting in blisters and superficial ulcerations.
Membrane boundXIIIα1(XIII)[α1(XIII)]3Skeletal muscle weakness.
XVIIα1(XVII)[α1(XVII)]3Atrophy of the skin and nonscarring blistering, epithelial dystrophy.
XXIIIα1(XXIII)[α1(XXIII)]3
XXVα1(XXV)[α1(XXV)]3Fibrosis of extraocular muscles, ophthalmoplegia.
MultiplexinsXVα1(XV)[α1(XV)]3
XVIIIα1(XVIII)[α1(XVIII)]3High myopia, vitreoretinal degeneration and occipital skull defects
OtherXXVIα1(XXVI)[α1(XXVI)]3
XXVIIIα1(XXVIII)[α1(XXVIII)]3
Table 2. Targeting with collagen. Matrikines and matricryptins: origin and pharmacological activities.
Table 2. Targeting with collagen. Matrikines and matricryptins: origin and pharmacological activities.
CollagenChainMatrikine/Matricryptin
Registered in ClinicalTrials.org
Activity
Iα1p1158/59Potentiates the remodeling of aorta wall after thrombosis
IVα1ArrestenAntiangiogenic
α2CanstatinAntiangiogenic. Inhibits the production of ROS and the elevation of intracellular Ca2+ levels. Antifibrotic
α3TumstatinAntiangiogenic
Tumstatin-peptide T7Cytotoxic
Tumstatin-peptide T3Improves heart function and reduces heart hypertrophy, fibrosis, and oxidative stress after myocardial infarction
Tumstatin-transferrin fusion
polypeptide: OCU200
Inhibits endothelial cell proliferation and damage in an oxygen-induced retinopathy
α4Tetrastatin-2Antiangiogenic
Tetrastatin peptide QS-13Antiangiogenic. Antimigratory
α5Pentastatin-1Antiangiogenic. Antitumoral
Lamstatin Inhibits lymphangiogenesis
Lamstatin peptide CP17
α6HexastatinAntiangiogenic. Antitumoral
VIIIα1VastatinAntiangiogenic. Antitumoral
XVα1RestinAntiangiogenic. Antitumoral
XVIIIα1EndostatinAntiangiogenic. Antitumoral
PEGylated endostatin M2ES
Endostar™ (recombinant endostatin approved in China)
Endostatin-derived E3 peptideAntifibrotic
E3 analogue END55
XIXα1Peptide F4Antiangiogenic. Antimetastatic
Table 3. Pharmacology of collagen: treatments assayed in clinical trials.
Table 3. Pharmacology of collagen: treatments assayed in clinical trials.
GroupDrug (Type)Clinical Trial DiseaseRefs
DirectCollagenase from
Clostridium histolyticum
MarketedFibrosis: Dupuytren’s contracture[42,43,44]
Fibrosis: Peyronie’s disease[45]
Debriding chronic dermal ulcers and
severely burned areas
[51,52]
Phase II:
efficacy not proven
Adhesive capsulitis of the shoulder[46]
IndirectMMPs inhibitors (12)Phase I–III:
efficacy not proven
Cancer[55,56]
Macular degeneration
Arthritis
Inflammation
MMP-9 inhibitorPhase II and III:
efficacy not proven
Gastric Cancer, Advanced Gastric, or GEJ Adenocarcinoma[57,58]
Phase II:
efficacy not proven
Crohn’s Disease[59]
mimic of miR-29Phase II:
efficacy not proven
Keloid formation[88,89]
anti-Grp78Phase I:
favorable safety profile
Refractory multiple myeloma[116]
HSP47 siRNAPhase II:
promising results
Hepatic fibrosis secondary to HCV infection[124]
Anti-LOXL2Phase II: efficacy not provenIdiopathic pulmonary fibrosis[149]
Primary sclerosing cholangitis[150]
Primary myelofibrosis[151]
Myelofibrosis secondary to
polycythemia vera
[151]
Essential thrombocythemia[151]
Bridging Fibrosis or Compensated Cirrhosis Caused by Nonalcoholic Steatohepatitis[152]
Liver fibrosis in HIV and HCV-infected adults[153]
Steatohepatitis pancreatic adenocarcinoma[154]
Metastatic KRAS mutant colorectal cancer[155]
Broad-spectrum LOX
inhibitors
Phase I/II:
promising results
Myelofibrosis[159]
Collagen
Peptides
Tumstatin based drugs [α3(IV)]Phase I: Diabetic macular edema[186]
Endostatin, PEGylated endostatin [α1(XVIII)]Phase III—marketedCancer[205]
Gene therapyRecombinant COL7A1 expressionMarketedDystrophic epidermolysis bullosa[219,220]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Revert-Ros, F.; Ventura, I.; Prieto-Ruiz, J.A.; Hernández-Andreu, J.M.; Revert, F. The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen. Int. J. Mol. Sci. 2024, 25, 6523. https://doi.org/10.3390/ijms25126523

AMA Style

Revert-Ros F, Ventura I, Prieto-Ruiz JA, Hernández-Andreu JM, Revert F. The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen. International Journal of Molecular Sciences. 2024; 25(12):6523. https://doi.org/10.3390/ijms25126523

Chicago/Turabian Style

Revert-Ros, Francisco, Ignacio Ventura, Jesús A. Prieto-Ruiz, José Miguel Hernández-Andreu, and Fernando Revert. 2024. "The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen" International Journal of Molecular Sciences 25, no. 12: 6523. https://doi.org/10.3390/ijms25126523

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop