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Biomolecules
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Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities
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Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities

A special issue of Biomolecules (ISSN 2218-273X).

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 26491

Special Issue Editor

Prof. Katalin Csiszar, Ph.D.

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Guest Editor
Department of Integrative Medicine and Quantitative Health Sciences, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA
Interests: lysyl oxidases; cell–extracellular matrix (ECM) signaling pathways; ECM-associated genetic disorders

Special Issue Information

Dear Colleagues,

Lysyl oxidase (LOX), a copper-dependent amine oxidase, known for its essential role in the assembly of the extracellular matrix (ECM), and four closely related LOX-like proteins (LOXL1-4) also functioning in the ECM, attracted considerable interest in the past decade as reports emerged supporting their involvement in cellular roles and in various disorders. Lysyl oxidases (LOXs), through multiple functions, have been shown to contribute to malignancies, including breast, ovarian, liver, lung, gastric, and pancreatic cancers. LOXL1 gene polymorphisms are associated with pseudoexfoliation (PEX) syndrome and PEX glaucoma, systematic screening of the LOXL genes identified LOXL2 as a susceptibility gene for intracranial aneurysms, a homozygous LOXL3 gene mutation was linked to autosomal recessive Stickler syndrome, and LOXL4 SNPs have been implicated in increased risk for endometriosis and associated infertility. The aberrant expression and activity of LOXs can modify the tumor microenvironment and cell–stroma interactions resulting in biochemical and biophysical cues, such as EMC stiffness, which promote tumor cell spreading and metastasis. Increased expression and activities of LOXs can influence the cell transcriptome, play prominent roles in fibrotic disorders of the dermis, lung and liver, and were noted in disorders of cardiac, epithelial, and musculoskeletal tissues. Regulation of the expression and activity of LOXs prominently involve the TGF-b regulatory loop, and numerous pathways, such as the MAPK pathways, ERK1/2, JNK, TNF-alpha, NF-kB, HIF2 and BMP2. LOXs also actively contribute to and/or modify signaling pathways, such as TGF-b/Smad2/3 and EGF.

This Special Issue will highlight the most recent developments in the LOX and LOXL field and offers an open access forum for new perspectives, including reviews and publications of original results of basic, applied, and clinical research. Contributions covering wide-ranging aspects of LOX and the LOXL1-4 proteins are welcome, including gene regulation, allelic variants implicated in various disorders, protein structure, isoforms, expression, processing and activation, regulation of catalytic activity, ECM and cellular functions, including those of the LOX-pro-peptide, and involvement of the LOX and LOXL1-4 proteins in signaling and regulatory pathways under normal and pathological conditions. We also welcome reports on specific inhibitors and their potential therapeutic applications in disorders with aberrant expression of LOXs.

Prof. Katalin Csiszar, Ph.D.
Guest Editor

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Extracellular matrix
  • Metastatic niche
  • Epithelial to mesenchymal transition
  • Cell–ECM signaling
  • Vascular and cardiac tissues
  • Dermal and musculoskeletal tissues
  • Fibrosis
  • LOX inhibitors

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Published Papers (4 papers)

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Research

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13 pages, 3939 KiB  
Article
Oligomeric States and Hydrodynamic Properties of Lysyl Oxidase-Like 2
by Alex A. Meier, Hee-Jung Moon, Ronald Toth IV, Ewa Folta-Stogniew, Krzysztof Kuczera, C. Russell Middaugh and Minae Mure
Biomolecules 2021, 11(12), 1846; https://doi.org/10.3390/biom11121846 - 8 Dec 2021
Cited by 7 | Viewed by 3326
Abstract
Lysyl oxidase-like 2 (LOXL2) has emerged as a promising therapeutic target against metastatic/invasive tumors and organ and tissue fibrosis. LOXL2 catalyzes the oxidative deamination of lysine and hydroxylysine residues in extracellular matrix (ECM) proteins to promote crosslinking of these proteins, and thereby plays [...] Read more.
Lysyl oxidase-like 2 (LOXL2) has emerged as a promising therapeutic target against metastatic/invasive tumors and organ and tissue fibrosis. LOXL2 catalyzes the oxidative deamination of lysine and hydroxylysine residues in extracellular matrix (ECM) proteins to promote crosslinking of these proteins, and thereby plays a major role in ECM remodeling. LOXL2 secretes as 100-kDa full-length protein (fl-LOXL2) and then undergoes proteolytic cleavage of the first two scavenger receptor cysteine-rich (SRCR) domains to yield 60-kDa protein (Δ1-2SRCR-LOXL2). This processing does not affect the amine oxidase activity of LOXL2 in vitro. However, the physiological importance of this cleavage still remains elusive. In this study, we focused on characterization of biophysical properties of fl- and Δ1-2SRCR-LOXL2s (e.g., oligomeric states, molecular weights, and hydrodynamic radii in solution) to gain insight into the structural role of the first two SRCR domains. Our study reveals that fl-LOXL2 exists predominantly as monomer but also dimer to the lesser extent when its concentration is <~1 mM. The hydrodynamic radius (Rh) determined by multi-angle light scattering coupled with size exclusion chromatography (SEC-MALS) indicates that fl-LOXL2 is a moderately asymmetric protein. In contrast, Δ1-2SRCR-LOXL2 exists solely as monomer and its Rh is in good agreement with the predicted value. The Rh values calculated from a 3D modeled structure of fl-LOXL2 and the crystal structure of the precursor Δ1-2SRCR-LOXL2 are within a reasonable margin of error of the values determined by SEC-MALS for fl- and Δ1-2SRCR-LOXL2s in mature forms in this study. Based on superimposition of the 3D model and the crystal structure of Δ1-2SRCR-LOXL2 (PDB:5ZE3), we propose a configuration of fl-LOXL2 that explains the difference observed in Rh between fl- and Δ1-2SRCR-LOXL2s in solution. Full article
(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)
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19 pages, 2829 KiB  
Article
Dill Extract Induces Elastic Fiber Neosynthesis and Functional Improvement in the Ascending Aorta of Aged Mice with Reversal of Age-Dependent Cardiac Hypertrophy and Involvement of Lysyl Oxidase-Like-1
by Wassim Fhayli, Quentin Boëté, Nadjib Kihal, Valérie Cenizo, Pascal Sommer, Walter A. Boyle, Marie-Paule Jacob and Gilles Faury
Biomolecules 2020, 10(2), 173; https://doi.org/10.3390/biom10020173 - 23 Jan 2020
Cited by 13 | Viewed by 6590
Abstract
Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular [...] Read more.
Elastic fibers (90% elastin, 10% fibrillin-rich microfibrils) are synthesized only in early life and adolescence mainly by the vascular smooth muscle cells through the cross-linking of its soluble precursor, tropoelastin. Elastic fibers endow the large elastic arteries with resilience and elasticity. Normal vascular aging is associated with arterial remodeling and stiffening, especially due to the end of production and degradation of elastic fibers, leading to altered cardiovascular function. Several pharmacological treatments stimulate the production of elastin and elastic fibers. In particular, dill extract (DE) has been demonstrated to stimulate elastin production in vitro in dermal equivalent models and in skin fibroblasts to increase lysyl oxidase–like-1 (LOXL-1) gene expression, an enzyme contributing to tropoelastin crosslinking and elastin formation. Here, we have investigated the effects of a chronic treatment (three months) of aged male mice with DE (5% or 10% v/v, in drinking water) on the structure and function of the ascending aorta. DE treatment, especially at 10%, of aged mice protected pre-existing elastic lamellae, reactivated tropoelastin and LOXL-1 expressions, induced elastic fiber neo-synthesis, and decreased the stiffness of the aging aortic wall, probably explaining the reversal of the age-related cardiac hypertrophy also observed following the treatment. DE could thus be considered as an anti-aging product for the cardiovascular system. Full article
(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)
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Review

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16 pages, 302 KiB  
Review
Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways
by Rozalia Laczko and Katalin Csiszar
Biomolecules 2020, 10(8), 1093; https://doi.org/10.3390/biom10081093 - 22 Jul 2020
Cited by 71 | Viewed by 8210
Abstract
Cu-dependent lysyl oxidase (LOX) plays a catalytic activity-related, primary role in the assembly of the extracellular matrix (ECM), a dynamic structural and regulatory framework which is essential for cell fate, differentiation and communication during development, tissue maintenance and repair. LOX, additionally, plays both [...] Read more.
Cu-dependent lysyl oxidase (LOX) plays a catalytic activity-related, primary role in the assembly of the extracellular matrix (ECM), a dynamic structural and regulatory framework which is essential for cell fate, differentiation and communication during development, tissue maintenance and repair. LOX, additionally, plays both activity-dependent and independent extracellular, intracellular and nuclear roles that fulfill significant functions in normal tissues, and contribute to vascular, cardiac, pulmonary, dermal, placenta, diaphragm, kidney and pelvic floor disorders. LOX activities have also been recognized in glioblastoma, diabetic neovascularization, osteogenic differentiation, bone matrix formation, ligament remodeling, polycystic ovary syndrome, fetal membrane rupture and tumor progression and metastasis. In an inflammatory context, LOX plays a role in diminishing pluripotent mesenchymal cell pools which are relevant to the pathology of diabetes, osteoporosis and rheumatoid arthritis. Most of these conditions involve mechanisms with complex cell and tissue type-specific interactions of LOX with signaling pathways, not only as a regulatory target, but also as an active player, including LOX-mediated alterations of cell surface receptor functions and mutual regulatory activities within signaling loops. In this review, we aim to provide insight into the diverse ways in which LOX participates in signaling events, and explore the mechanistic details and functional significance of the regulatory and cross-regulatory interactions of LOX with the EGFR, PDGF, VEGF, TGF-β, mechano-transduction, inflammatory and steroid signaling pathways. Full article
(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)
21 pages, 3200 KiB  
Review
Emerging Roles of Lysyl Oxidases in the Cardiovascular System: New Concepts and Therapeutic Challenges
by José Martínez-González, Saray Varona, Laia Cañes, María Galán, Ana M Briones, Victoria Cachofeiro and Cristina Rodríguez
Biomolecules 2019, 9(10), 610; https://doi.org/10.3390/biom9100610 - 14 Oct 2019
Cited by 45 | Viewed by 7525
Abstract
Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. [...] Read more.
Lysyl oxidases (LOX and LOX-likes (LOXLs) isoenzymes) belong to a family of copper-dependent enzymes classically involved in the covalent cross-linking of collagen and elastin, a pivotal process that ensures extracellular matrix (ECM) stability and provides the tensile and elastic characteristics of connective tissues. Besides this structural role, in the last years, novel biological properties have been attributed to these enzymes, which can critically influence cardiovascular function. LOX and LOXLs control cell proliferation, migration, adhesion, differentiation, oxidative stress, and transcriptional regulation and, thereby, their dysregulation has been linked to a myriad of cardiovascular pathologies. Lysyl oxidase could modulate virtually all stages of the atherosclerotic process, from endothelial dysfunction and plaque progression to calcification and rupture of advanced and complicated plaques, and contributes to vascular stiffness in hypertension. The alteration of LOX/LOXLs expression underlies the development of other vascular pathologies characterized by a destructive remodeling of the ECM, such as aneurysm and artery dissections, and contributes to the adverse myocardial remodeling and dysfunction in hypertension, myocardial infarction, and obesity. This review examines the most recent advances in the study of LOX and LOXLs biology and their pathophysiological role in cardiovascular diseases with special emphasis on their potential as therapeutic targets. Full article
(This article belongs to the Special Issue Lysyl Oxidases: Novel Roles in Disease and Therapeutic Opportunities)
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