International Journal of Molecular Sciences

Research

Jump to: Review

29 pages, 11746 KiB

Open AccessArticle

In Vitro Model to Investigate Communication between Dorsal Root Ganglion and Spinal Cord Glia

by Junxuan Ma, Vaibhav Patil, Abhay Pandit, Leo R. Quinlan, David P. Finn, Sibylle Grad, Mauro Alini and Marianna Peroglio

Int. J. Mol. Sci. 2021, 22(18), 9725; https://doi.org/10.3390/ijms22189725 - 8 Sep 2021

Cited by 9 | Viewed by 3301

Abstract

Chronic discogenic back pain is associated with increased inflammatory cytokine levels that can influence the proximal peripheral nervous system, namely the dorsal root ganglion (DRG). However, transition to chronic pain is widely thought to involve glial activation in the spinal cord. In this [...] Read more.

Chronic discogenic back pain is associated with increased inflammatory cytokine levels that can influence the proximal peripheral nervous system, namely the dorsal root ganglion (DRG). However, transition to chronic pain is widely thought to involve glial activation in the spinal cord. In this study, an in vitro model was used to evaluate the communication between DRG and spinal cord glia. Primary neonatal rat DRG cells were treated with/without inflammatory cytokines (TNF-α, IL-1β, and IL-6). The conditioned media were collected at two time points (12 and 24 h) and applied to spinal cord mixed glial culture (MGC) for 24 h. Adult bovine DRG and spinal cord cell cultures were also tested, as an alternative large animal model, and results were compared with the neonatal rat findings. Compared with untreated DRG-conditioned medium, the second cytokine-treated DRG-conditioned medium (following medium change, thus containing solely DRG-derived molecules) elevated CD11b expression and calcium signal in neonatal rat microglia and enhanced Iba1 expression in adult bovine microglia. Cytokine treatment induced a DRG-mediated microgliosis. The described in vitro model allows the use of cells from large species and may represent an alternative to animal pain models (3R principles). Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Graphical abstract

14 pages, 4975 KiB

Open AccessArticle

A Hyaluronan and Platelet-Rich Plasma Hydrogel for Mesenchymal Stem Cell Delivery in the Intervertebral Disc: An Organ Culture Study

by Fabrizio Russo, Luca Ambrosio, Marianna Peroglio, Wei Guo, Sebastian Wangler, Jan Gewiess, Sibylle Grad, Mauro Alini, Rocco Papalia, Gianluca Vadalà and Vincenzo Denaro

Int. J. Mol. Sci. 2021, 22(6), 2963; https://doi.org/10.3390/ijms22062963 - 15 Mar 2021

Cited by 27 | Viewed by 3359

Abstract

The purpose of the present pilot study was to evaluate the effect of a hydrogel composed of hyaluronic acid (HA) and platelet-rich plasma (PRP) as a carrier for human mesenchymal stem cells (hMSCs) for intervertebral disc (IVD) regeneration using a disc organ culture [...] Read more.

The purpose of the present pilot study was to evaluate the effect of a hydrogel composed of hyaluronic acid (HA) and platelet-rich plasma (PRP) as a carrier for human mesenchymal stem cells (hMSCs) for intervertebral disc (IVD) regeneration using a disc organ culture model. HA was mixed with batroxobin (BTX) and PRP to form a hydrogel encapsulating 1 × 10⁶ or 2 × 10⁶ hMSCs. Bovine IVDs were nucleotomized and filled with hMSCs suspended in ~200 μL of the PRP/HA/BTX hydrogel. IVDs collected at day 0 and nucleotomized IVDs with no hMSCs and/or hydrogel alone were used as controls. hMSCs encapsulated in the hydrogel were also cultured in well plates to evaluate the effect of the IVD environment on hMSCs. After 1 week, tissue structure, scaffold integration, hMSC viability and gene expression of matrix and nucleus pulposus (NP) cell markers were assessed. Histological analysis showed a better preservation of the viability of the IVD tissue adjacent to the gel in the presence of hMSCs (~70%) compared to the hydrogel without hMSCs. Furthermore, disc morphology was maintained, and the hydrogel showed signs of integration with the surrounding tissues. At the gene expression level, the hydrogel loaded with hMSCs preserved the normal metabolism of the tissue. The IVD environment promoted hMSC differentiation towards a NP cell phenotype by increasing cytokeratin-19 (KRT19) gene expression. This study demonstrated that the hydrogel composed of HA/PRP/BTX represents a valid carrier for hMSCs being able to maintain a good cell viability while stimulating cell activity and NP marker expression. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

16 pages, 3635 KiB

Open AccessArticle

Pro-Inflammatory and Neurotrophic Factor Responses of Cells Derived from Degenerative Human Intervertebral Discs to the Opportunistic Pathogen Cutibacterium acnes

by Manu N. Capoor, Anna Konieczna, Andrew McDowell, Filip Ruzicka, Martin Smrcka, Radim Jancalek, Karel Maca, Michael Lujc, Fahad S. Ahmed, Christof Birkenmaier, Stefan Dudli and Ondrej Slaby

Int. J. Mol. Sci. 2021, 22(5), 2347; https://doi.org/10.3390/ijms22052347 - 26 Feb 2021

Cited by 15 | Viewed by 2937

Abstract

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1β, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes [...] Read more.

Previously, we proposed the hypothesis that similarities in the inflammatory response observed in acne vulgaris and degenerative disc disease (DDD), especially the central role of interleukin (IL)-1β, may be further evidence of the role of the anaerobic bacterium Cutibacterium (previously Propionibacterium) acnes in the underlying aetiology of disc degeneration. To investigate this, we examined the upregulation of IL-1β, and other known IL-1β-induced inflammatory markers and neurotrophic factors, from nucleus-pulposus-derived disc cells infected in vitro with C. acnes for up to 48 h. Upon infection, significant upregulation of IL-1β, alongside IL-6, IL-8, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 4 (CCL4), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), was observed with cells isolated from the degenerative discs of eight patients versus non-infected controls. Expression levels did, however, depend on gene target, multiplicity and period of infection and, notably, donor response. Pre-treatment of cells with clindamycin prior to infection significantly reduced the production of pro-inflammatory mediators. This study confirms that C. acnes can stimulate the expression of IL-1β and other host molecules previously associated with pathological changes in disc tissue, including neo-innervation. While still controversial, the role of C. acnes in DDD remains biologically credible, and its ability to cause disease likely reflects a combination of factors, particularly individualised response to infection. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

15 pages, 3004 KiB

Open AccessArticle

The Role of Panx3 in Age-Associated and Injury-Induced Intervertebral Disc Degeneration

by Meaghan Serjeant, Paxton M. Moon, Diana Quinonez, Silvia Penuela, Frank Beier and Cheryle A. Séguin

Int. J. Mol. Sci. 2021, 22(3), 1080; https://doi.org/10.3390/ijms22031080 - 22 Jan 2021

Cited by 11 | Viewed by 2992

Abstract

Pannexin 3 (Panx3) is a mechanosensitive, channel-forming glycoprotein implicated in the progression of post-traumatic osteoarthritis. Despite evidence for Panx3 expression in the intervertebral disc (IVD), its function in this cartilaginous joint structure remained unknown. Using Panx3 knockout mice, this study investigated the role [...] Read more.

Pannexin 3 (Panx3) is a mechanosensitive, channel-forming glycoprotein implicated in the progression of post-traumatic osteoarthritis. Despite evidence for Panx3 expression in the intervertebral disc (IVD), its function in this cartilaginous joint structure remained unknown. Using Panx3 knockout mice, this study investigated the role of Panx3 in age-associated IVD degeneration and degeneration induced by annulus fibrosus (AF) needle puncture. Loss of Panx3 did not significantly impact the progression of age-associated histopathological IVD degeneration; however, loss of Panx3 was associated with decreased gene expression of Acan, Col1a1, Mmp13 and Runx2 and altered localization of COLX in the IVD at 19 months-of-age. Following IVD injury in the caudal spine, histological analysis of wild-type mice revealed clusters of hypertrophic cells in the AF associated with increased pericellular proteoglycan accumulation, disruptions in lamellar organization and increased lamellar thickness. In Panx3 knockout mice, hypertrophic AF cells were rarely detected and AF structure was largely preserved post-injury. Interestingly, uninjured IVDs adjacent to the site of injury more frequently showed evidence of early nucleus pulposus degeneration in Panx3 knockout mice but remained healthy in wild-type mice. These findings suggest a role for Panx3 in mediating the adaptive cellular responses to altered mechanical stress in the IVD, which may buffer aberrant loads transferred to adjacent motion segments. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

15 pages, 2601 KiB

Open AccessArticle

Advanced Glycation End Product Inhibitor Pyridoxamine Attenuates IVD Degeneration in Type 2 Diabetic Rats

by Juliane D. Glaeser, Derek Ju, Wafa Tawackoli, Jae H. Yang, Khosrowdad Salehi, Tina Stefanovic, Linda E. A. Kanim, Pablo Avalos, Giselle Kaneda, Stephen Stephan, Melodie F. Metzger, Hyun W. Bae and Dmitriy Sheyn

Int. J. Mol. Sci. 2020, 21(24), 9709; https://doi.org/10.3390/ijms21249709 - 19 Dec 2020

Cited by 8 | Viewed by 2941

Abstract

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD [...] Read more.

Type 2 diabetes mellitus (T2DM) is associated with advanced glycation end product (AGE) enrichment and considered a risk factor for intervertebral disc (IVD) degeneration. We hypothesized that systemic AGE inhibition, achieved using pyridoxamine (PM), attenuates IVD degeneration in T2DM rats. To induce IVD degeneration, lumbar disc injury or sham surgery was performed on Zucker Diabetic Sprague Dawley (ZDSD) or control Sprague Dawley (SD) rats. Post-surgery, IVD-injured ZDSD rats received daily PM dissolved in drinking water or water only. The resulting groups were SD uninjured, SD injured, ZDSD uninjured, ZDSD injured, and ZDSD injured + PM. Levels of blood glycation and disc degeneration were investigated. At week 8 post-surgery, glycated serum protein (GSP) levels were increased in ZDSDs compared to SDs. PM treatment attenuated this increase. Micro-MRI analysis demonstrated IVD dehydration in injured versus uninjured SDs and ZDSDs. In the ZDSD injured + PM group, IVD dehydration was diminished compared to ZDSD injured. AGE levels were decreased and aggrecan levels increased in ZDSD injured + PM versus ZDSD injured rats. Histological and immunohistochemical analyses further supported the beneficial effect of PM. In summary, PM attenuated GSP levels and IVD degeneration processes in ZDSD rats, demonstrating its potential to attenuate IVD degeneration in addition to managing glycemia in T2DM. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Graphical abstract

17 pages, 6075 KiB

Open AccessArticle

Spheroid-Like Cultures for Expanding Angiopoietin Receptor-1 (aka. Tie2) Positive Cells from the Human Intervertebral Disc

by Xingshuo Zhang, Julien Guerrero, Andreas S. Croft, Christoph E. Albers, Sonja Häckel and Benjamin Gantenbein

Int. J. Mol. Sci. 2020, 21(24), 9423; https://doi.org/10.3390/ijms21249423 - 10 Dec 2020

Cited by 12 | Viewed by 2851

Abstract

Lower back pain is a leading cause of disability worldwide. The recovery of nucleus pulposus (NP) progenitor cells (NPPCs) from the intervertebral disc (IVD) holds high promise for future cell therapy. NPPCs are positive for the angiopoietin-1 receptor (Tie2) and possess stemness capacity. [...] Read more.

Lower back pain is a leading cause of disability worldwide. The recovery of nucleus pulposus (NP) progenitor cells (NPPCs) from the intervertebral disc (IVD) holds high promise for future cell therapy. NPPCs are positive for the angiopoietin-1 receptor (Tie2) and possess stemness capacity. However, the limited Tie2+ NPC yield has been a challenge for their use in cell-based therapy for regenerative medicine. In this study, we attempted to expand NPPCs from the whole NP cell population by spheroid-formation assay. Flow cytometry was used to quantify the percentage of NPPCs with Tie2-antibody in human primary NP cells (NPCs). Cell proliferation was assessed using the population doublings level (PDL) measurement. Synthesis and presence of extracellular matrix (ECM) from NPC spheroids were confirmed by quantitative Polymerase Chain Reaction (qPCR), immunostaining, and microscopy. Compared with monolayer, the spheroid-formation assay enriched the percentage of Tie2+ in NPCs’ population from ~10% to ~36%. Moreover, the spheroid-formation assay also inhibited the proliferation of the Tie2- NPCs with nearly no PDL. After one additional passage (P) using the spheroid-formation assay, NPC spheroids presented a Tie2+ percentage even further by ~10% in the NPC population. Our study concludes that the use of a spheroid culture system could be successfully applied to the culture and expansion of tissue-specific progenitors. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

13 pages, 2294 KiB

Open AccessArticle

Regenerative Response of Degenerate Human Nucleus Pulposus Cells to GDF6 Stimulation

by Tom Hodgkinson, Hamish T. J. Gilbert, Tej Pandya, Ashish D. Diwan, Judith A. Hoyland and Stephen M. Richardson

Int. J. Mol. Sci. 2020, 21(19), 7143; https://doi.org/10.3390/ijms21197143 - 27 Sep 2020

Cited by 11 | Viewed by 4290

Abstract

Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic [...] Read more.

Growth differentiation factor (GDF) family members have been implicated in the development and maintenance of healthy nucleus pulposus (NP) tissue, making them promising therapeutic candidates for treatment of intervertebral disc (IVD) degeneration and associated back pain. GDF6 has been shown to promote discogenic differentiation of mesenchymal stem cells, but its effect on NP cells remains largely unknown. Our aim was to investigate GDF6 signalling in adult human NP cells derived from degenerate tissue and determine the signal transduction pathways critical for GDF6-mediated phenotypic changes and tissue homeostatic mechanisms. This study demonstrates maintained expression of GDF6 receptors in human NP and annulus fibrosus (AF) cells across a range of degeneration grades at gene and protein level. We observed an anabolic response in NP cells treated with recombinant GDF6 (increased expression of matrix and NP-phenotypic markers; increased glycosaminoglycan production; no change in catabolic enzyme expression), and identified the signalling pathways involved in these responses (SMAD1/5/8 and ERK1/2 phosphorylation, validated by blocking studies). These findings suggest that GDF6 promotes a healthy disc tissue phenotype in degenerate NP cells through SMAD-dependent and -independent (ERK1/2) mechanisms, which is important for development of GDF6 therapeutic strategies for treatment of degenerate discs. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

15 pages, 689 KiB

Open AccessArticle

Serum Biomarkers for Connective Tissue and Basement Membrane Remodeling Are Associated with Vertebral Endplate Bone Marrow Lesions as Seen on MRI (Modic Changes)

by Stefan Dudli, Alexander Ballatori, Anne-Christine Bay-Jensen, Zachary L. McCormick, Conor W. O’Neill, Sibel Demir-Deviren, Roland Krug, Irina Heggli, Astrid Juengel, Jaro Karppinen, Florian Brunner, Mazda Farshad, Oliver Distler, Jeffrey C. Lotz and Aaron J. Fields

Int. J. Mol. Sci. 2020, 21(11), 3791; https://doi.org/10.3390/ijms21113791 - 27 May 2020

Cited by 16 | Viewed by 3498

Abstract

Vertebral endplate bone marrow lesions, visualized on magnetic resonance imaging (MRI) as Modic changes (MC), are associated with chronic low back pain (cLBP). Since guidelines recommend against routine spinal MRI for cLBP in primary care, MC may be underdiagnosed. Serum biomarkers for MC [...] Read more.

Vertebral endplate bone marrow lesions, visualized on magnetic resonance imaging (MRI) as Modic changes (MC), are associated with chronic low back pain (cLBP). Since guidelines recommend against routine spinal MRI for cLBP in primary care, MC may be underdiagnosed. Serum biomarkers for MC would allow early diagnosis, inform clinical care decisions, and supplement treatment monitoring. We aimed to discover biomarkers in the blood serum that correlate with MC pathophysiological processes. For this single-site cross-sectional study, we recruited 54 subjects with 38 cLBP patients and 16 volunteers without a history of LBP. All subjects completed an Oswestry Disability Index (ODI) questionnaire and 10-cm Visual Analog Score (VAS) for LBP (VASback) and leg pain. Lumbar T1-weighted and fat-saturated T2-weighted MRI were acquired at 3T and used for MC classification in each endplate. Blood serum was collected on the day of MRI. Biomarkers related to disc resorption and bone marrow fibrosis were analyzed with enzyme-linked immune-absorbent assays. The concentration of biomarkers between no MC and any type of MC (AnyMC), MC1, and MC2 were compared. The Area Under the Curve (AUC) of the Receiver Operating Characteristics were calculated for each biomarker and for bivariable biomarker models. We found that biomarkers related to type III and type IV collagen degradation and formation tended to correlate with the presence of MC (p = 0.060–0.088). The bivariable model with the highest AUC was PRO-C3 + C4M and had a moderate diagnostic value for AnyMC in cLBP patients (AUC = 0.73, specificity = 78.9%, sensitivity = 73.7%). In conclusion, serum biomarkers related to the formation and degradation of type III and type IV collagen, which are key molecules in bone marrow fibrosis, correlated with MC presence. Bone marrow fibrosis may be an important pathophysiological process in MC that should be targeted in larger biomarker and treatment studies. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

13 pages, 3050 KiB

Open AccessArticle

DI-5-Cuffs: Lumbar Intervertebral Disc Proteoglycan and Water Content Changes in Humans after Five Days of Dry Immersion to Simulate Microgravity

by Loïc Treffel, Nastassia Navasiolava, Karen Mkhitaryan, Emmanuelle Jouan, Kathryn Zuj, Guillemette Gauquelin-Koch, Marc-Antoine Custaud and Claude Gharib

Int. J. Mol. Sci. 2020, 21(11), 3748; https://doi.org/10.3390/ijms21113748 - 26 May 2020

Cited by 11 | Viewed by 3749

Abstract

Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry [...] Read more.

Most astronauts experience back pain after spaceflight, primarily located in the lumbar region. Intervertebral disc herniations have been observed after real and simulated microgravity. Spinal deconditioning after exposure to microgravity has been described, but the underlying mechanisms are not well understood. The dry immersion (DI) model of microgravity was used with eighteen male volunteers. Half of the participants wore thigh cuffs as a potential countermeasure. The spinal changes and intervertebral disc (IVD) content changes were investigated using magnetic resonance imaging (MRI) analyses with T1-T2 mapping sequences. IVD water content was estimated by the apparent diffusion coefficient (ADC), with proteoglycan content measured using MRI T1-mapping sequences centered in the nucleus pulposus. The use of thigh cuffs had no effect on any of the spinal variables measured. There was significant spinal lengthening for all of the subjects. The ADC and IVD proteoglycan content both increased significantly with DI (7.34 ± 2.23% and 10.09 ± 1.39%, respectively; mean ± standard deviation), p < 0.05). The ADC changes suggest dynamic and rapid water diffusion inside IVDs, linked to gravitational unloading. Further investigation is needed to determine whether similar changes occur in the cervical IVDs. A better understanding of the mechanisms involved in spinal deconditioning with spaceflight would assist in the development of alternative countermeasures to prevent IVD herniation. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

18 pages, 4850 KiB

Open AccessArticle

Bone Morphogenetic Proteins for Nucleus Pulposus Regeneration

by Anita Krouwels, Juvita D. Iljas, Angela H. M. Kragten, Wouter J. A. Dhert, F. Cumhur Öner, Marianna A. Tryfonidou and Laura B. Creemers

Int. J. Mol. Sci. 2020, 21(8), 2720; https://doi.org/10.3390/ijms21082720 - 14 Apr 2020

Cited by 12 | Viewed by 3673

Abstract

Matrix production by nucleus pulposus (NP) cells, the cells residing in the center of the intervertebral disc, can be stimulated by growth factors. Bone morphogenetic proteins (BMPs) hold great promise. Although BMP2 and BMP7 have been used most frequently, other BMPs have also [...] Read more.

Matrix production by nucleus pulposus (NP) cells, the cells residing in the center of the intervertebral disc, can be stimulated by growth factors. Bone morphogenetic proteins (BMPs) hold great promise. Although BMP2 and BMP7 have been used most frequently, other BMPs have also shown potential for NP regeneration. Heterodimers may be more potent than single homodimers, but it is not known whether combinations of homodimers would perform equally well. In this study, we compared BMP2, BMP4, BMP6, and BMP7, their combinations and heterodimers, for regeneration by human NP cells. The BMPs investigated induced variable matrix deposition by NP cells. BMP4 was the most potent, both in the final neotissue glysosaminoglycan content and incorporation efficiency. Heterodimers BMP2/6H and BMP2/7H were more potent than their respective homodimer combinations, but not the BMP4/7H heterodimer. The current results indicate that BMP4 might have a high potential for regeneration of the intervertebral disc. Moreover, the added value of BMP heterodimers over their respective homodimer BMP combinations depends on the BMP combination applied. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Graphical abstract

15 pages, 8605 KiB

Open AccessArticle

Adrenoceptor Expression during Intervertebral Disc Degeneration

by Johannes Kupka, Annika Kohler, Karima El Bagdadi, Richard Bostelmann, Marco Brenneis, Christoph Fleege, Danny Chan, Frank Zaucke, Andrea Meurer, Marcus Rickert and Zsuzsa Jenei-Lanzl

Int. J. Mol. Sci. 2020, 21(6), 2085; https://doi.org/10.3390/ijms21062085 - 18 Mar 2020

Cited by 12 | Viewed by 4258

Abstract

Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and [...] Read more.

Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Graphical abstract

Review

Jump to: Research

45 pages, 2210 KiB

Open AccessReview

Multiscale Regulation of the Intervertebral Disc: Achievements in Experimental, In Silico, and Regenerative Research

by Laura Baumgartner, Karin Wuertz-Kozak, Christine L. Le Maitre, Francis Wignall, Stephen M. Richardson, Judith Hoyland, Carlos Ruiz Wills, Miguel A. González Ballester, Michael Neidlin, Leonidas G. Alexopoulos and Jérôme Noailly

Int. J. Mol. Sci. 2021, 22(2), 703; https://doi.org/10.3390/ijms22020703 - 12 Jan 2021

Cited by 29 | Viewed by 6770

Abstract

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the [...] Read more.

Intervertebral disc (IVD) degeneration is a major risk factor of low back pain. It is defined by a progressive loss of the IVD structure and functionality, leading to severe impairments with restricted treatment options due to the highly demanding mechanical exposure of the IVD. Degenerative changes in the IVD usually increase with age but at an accelerated rate in some individuals. To understand the initiation and progression of this disease, it is crucial to identify key top-down and bottom-up regulations’ processes, across the cell, tissue, and organ levels, in health and disease. Owing to unremitting investigation of experimental research, the comprehension of detailed cell signaling pathways and their effect on matrix turnover significantly rose. Likewise, in silico research substantially contributed to a holistic understanding of spatiotemporal effects and complex, multifactorial interactions within the IVD. Together with important achievements in the research of biomaterials, manifold promising approaches for regenerative treatment options were presented over the last years. This review provides an integrative analysis of the current knowledge about (1) the multiscale function and regulation of the IVD in health and disease, (2) the possible regenerative strategies, and (3) the in silico models that shall eventually support the development of advanced therapies. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

23 pages, 1083 KiB

Open AccessReview

Intervertebral Disc and Adipokine Leptin—Loves Me, Loves Me Not

by Goran Curic

Int. J. Mol. Sci. 2021, 22(1), 375; https://doi.org/10.3390/ijms22010375 - 31 Dec 2020

Cited by 10 | Viewed by 3119

Abstract

Leptin—the most famous adipose tissue-secreted hormone—in the human body is mostly observed in a negative connotation, as the hormone level increases with the accumulation of body fat. Nowadays, fatness is becoming another normal body shape. Fatness is burdened with numerous illnesses—including low back [...] Read more.

Leptin—the most famous adipose tissue-secreted hormone—in the human body is mostly observed in a negative connotation, as the hormone level increases with the accumulation of body fat. Nowadays, fatness is becoming another normal body shape. Fatness is burdened with numerous illnesses—including low back pain and degenerative disease of lumbar intervertebral disc (IVD). IVD degeneration and IVD inflammation are two indiscerptible phenomena. Irrespective of the underlying pathophysiological background (trauma, obesity, nutrient deficiency), the inflammation is crucial in triggering IVD degeneration. Leptin is usually depicted as a proinflammatory adipokine. Many studies aimed at explaining the role of leptin in IVD degeneration, though mostly in in vitro and on animal models, confirmed leptin’s “bad reputation”. However, several studies found that leptin might have protective role in IVD metabolism. This review examines the current literature on the metabolic role of different depots of adipose tissue, with focus on leptin, in pathogenesis of IVD degeneration. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

15 pages, 837 KiB

Open AccessReview

MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology

by Petra Cazzanelli and Karin Wuertz-Kozak

Int. J. Mol. Sci. 2020, 21(10), 3601; https://doi.org/10.3390/ijms21103601 - 20 May 2020

Cited by 154 | Viewed by 8672

Abstract

Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), [...] Read more.

Intervertebral disc (IVD) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on IVD degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of protein-coding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

32 pages, 3547 KiB

Open AccessReview

Intervertebral Disc Diseases PART 2: A Review of the Current Diagnostic and Treatment Strategies for Intervertebral Disc Disease

by Pang Hung Wu, Hyeun Sung Kim and Il-Tae Jang

Int. J. Mol. Sci. 2020, 21(6), 2135; https://doi.org/10.3390/ijms21062135 - 20 Mar 2020

Cited by 132 | Viewed by 18833

Abstract

With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for [...] Read more.

With an aging population, there is a proportional increase in the prevalence of intervertebral disc diseases. Intervertebral disc diseases are the leading cause of lower back pain and disability. With a high prevalence of asymptomatic intervertebral disc diseases, there is a need for accurate diagnosis, which is key to management. A thorough understanding of the pathophysiology and clinical manifestation aids in understanding the natural history of these conditions. Recent developments in radiological and biomarker investigations have potential to provide noninvasive alternatives to the gold standard, invasive discogram. There is a large volume of literature on the management of intervertebral disc diseases, which we categorized into five headings: (a) Relief of pain by conservative management, (b) restorative treatment by molecular therapy, (c) reconstructive treatment by percutaneous intervertebral disc techniques, (d) relieving compression and replacement surgery, and (e) rigid fusion surgery. This review article aims to provide an overview on various current diagnostic and treatment options and discuss the interplay between each arms of these scientific and treatment advancements, hence providing an outlook of their potential future developments and collaborations in the management of intervertebral disc diseases. Full article

(This article belongs to the Special Issue Intervertebral Disc Disease: From Pathophysiology to Novel Therapies)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Intervertebral Disc Disease: From Pathophysiology to Novel Therapies

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (15 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI