Syndecan-4 in intervertebral disc and cartilage: Saint or synner? (original) (raw)
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Matrix synthesis and degradation in human intervertebral disc degeneration
Biochemical Society Transactions, 2007
Degeneration of the intervertebral disc has been implicated in chronic low back pain. Type II collagen and proteoglycan (predominantly aggrecan) content is crucial to proper disc function, particularly in the nucleus pulposus. In degeneration, synthesis of matrix molecules changes, leading to an increase in the synthesis of collagens type I and III and a decreased production of aggrecan. Linked to this is an increased expression of matrix-degrading molecules including MMPs (matrix metalloproteinases) and the aggrecanases, ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) 1, 4, 5, 9 and 15, all of which are produced by native disc cells. Importantly, we have found that there is a net increase in these molecules, over their natural inhibitors [TIMP-1 (tissue inhibitor of metalloproteinases-1), 2 and 3], suggesting a deregulation of the normal homoeostatic mechanism. Growth factors and cytokines [particularly TNFα (tumour necrosis factor α) and IL-1 (interleukin 1)] have been implicated in the regulation of this catabolic process. Our work has shown that in degenerate discs there is an increase in IL-1, but no corresponding increase in the inhibitor IL-1 receptor antagonist. Furthermore, treatment of human disc cells with IL-1 leads to a decrease in matrix gene expression and increased MMP and ADAMTS expression. Inhibition of IL-1 would therefore be an important therapeutic target for preventing/reversing disc degeneration.
Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society, 2000
To determine the steady-state of messenger RNA (mRNA) levels of syndecan-1 and syndecan-4 in cartilage samples and chondrocytes derived from human osteoarthritic knee joints. Steady-state levels of gene-specific mRNA (relative to beta-actin) were measured by semiquantitative polymerase chain reaction (PCR). RT-PCR allowed detection of syndecan-1 (for the first time) and syndecan-4 in both cartilage samples and articular chondrocytes cultured as primary monolayers. The mRNA levels of syndecan-1 were reduced in cartilage tissue from heavily damaged compared to normal-looking areas whereas those of syndecan-4 were significantly increased. In contrast, the expression of syndecan-1 was higher in cultured chondrocytes derived from the fibrillated osteoarthritic cartilage than in cells obtained from intact cartilage, while the syndecan-4 message levels did not differ between the two sites. The expression of the cell-surface syndecans 1 and 4 is altered during the osteoarthritic degradative...
Arthritis Research & Therapy, 2009
Introduction The aim of this study was to compare the effects of tumour necrosis factor-alpha (TNF-α) and interleukin-1-beta (IL-1β) on protease and catabolic cytokine and receptor gene expression in normal and degenerate human nucleus pulposus cells in alginate culture. Methods Cells isolated from normal and degenerate nucleus pulposus regions of human intervertebral discs were cultured in alginate pellets and stimulated by the addition of 10 ng/mL TNFα or IL-1β for 48 hours prior to RNA extraction. Quantitative realtime polymerase chain reaction was used to assess the effect of TNF-α or IL-β stimulation on the expression of matrix metalloproteinase (MMP)-3,-9 and-13, TNF-α, TNF receptor 1 (TNF-R1), TNF receptor 2 (TNF-R2), IL-1α, IL-1β, IL-1 receptor 1 (IL-1R1) and IL-1 receptor antagonist (IL-1Ra). Results MMP-3 and MMP-9 gene expressions were upregulated to a greater level by IL-1β than TNF-α. MMP-13 was upregulated by each cytokine to a similar extent. TNF-α and TNF-R2 expressions were upregulated by both TNF-α and IL-β, whereas TNF-R1 expression was not significantly affected by either cytokine. IL-1β and IL-1Ra expressions were significantly upregulated by TNF-α, whereas IL-1α and IL-1R1 were unchanged. Conclusions TNF-α does not induce MMP expression to the same degree as stimulation by IL-1β, but it does act to upregulate IL-1β expression as well as TNF-α and TNF-R2. The net result of this would be an increased inflammatory environment and accelerated degradation of the matrix. These results support the hypothesis that, while TNF-α may be an important initiating factor in matrix degeneration, IL-1β plays a greater role in established pathological degradation.
Investigation of the role of IL-1 and TNF in matrix degradation in the intervertebral disc
Rheumatology, 2008
Objective. To establish if IL-1 or TNF regulates matrix degradation in the non-degenerate or degenerate intervertebral disc (IVD). Methods. In situ zymography (ISZ) has been used to investigate the role of IL-1 and TNF in the matrix degradation characterizing symptomatic IVD degeneration. ISZ employed three substrates (gelatin, collagen II, casein) and four different challenges, IL-1, IL-1 receptor antagonist (IL-1Ra), TNF-and anti-TNF. Results. We have shown for the first time that whilst IL-1 will stimulate and IL-1 receptor antagonist will inhibit matrix degradation in intact human IVD tissue, neither TNF-nor anti-TNF have any measurable effect on degradation of these matrices. Conclusion. This study has addressed a current area of controversy in IVD biology, namely, whether either IL-1 or TNF or both are involved in driving matrix degradation. Our data indicate that IL-1 is a key cytokine mediating matrix degradation in the IVD and therefore a therapeutic target.
Cell Biochemistry and Function, 2006
Alterations in the composition of intervertebral disc extracellular matrix, mainly collagen and proteoglycans, may cause changes in mechanical properties of the disc, leading to dysfunction, nerve root compression, and herniation with severe clinical manifestations. Matrix metalloproteinases may be involved in degradation by hydrolysing extracellular matrix components. Inhibitors of matrix metalloproteinases, in contrast, function in the maintenance of degradation control. In this study, we investigated: (i) whether the level of matrix degradation correlated with the duration of the symptomatic disease, (ii) roles of matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) in intervertebral disc degeneration. Nucleus pulposus of intervertebral discs were obtained from 22 patients and analysed for collagen and proteoglycan contents, and pro-MMP-2, TIMP-2 levels. Collagen content was determined as hydroxyproline and proteoglycan content was measured as glycosaminoglycans. The loss in matrix components did not correlate with the duration of the degenerative disc disease. Pro-MMP-2 levels were higher at early stages of the degenerative disc disease (r ¼ À0.495, P < 0.05). TIMP-2 levels were similar in all samples. Pro-MMP-2 and TIMP-2 levels negatively correlated in herniated discs samples (r ¼ À0.855, P < 0.01). Pro-MMP-2 levels negatively correlated with the collagen content in herniated disc material. Our findings may suggest a silent period of active disease prior to symptomatic outcome during which irreversible matrix loss occurs. Involvement of other proteolytic enzymes at different stages of the disease should also be investigated to help to control the degradation cascade at relatively early stages of disc degeneration before the clinical onset of disease.
Inflammation in intervertebral disc degeneration and regeneration
Journal of the Royal Society, Interface / the Royal Society, 2015
Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overv...
Arthritis research & therapy, 2017
Lubricin/proteoglycan 4 (PRG4) is a mucinous glycoprotein secreted by synovial fibroblasts and superficial zone chondrocytes. Recently, we showed that recombinant human PRG4 (rhPRG4) is a putative ligand for CD44 receptor. rhPRG4-CD44 interaction inhibits cytokine-induced rheumatoid arthritis synoviocyte proliferation. The objective of this study is to decipher the autocrine function of PRG4 in regulating osteoarthritic synoviocyte proliferation and expression of catabolic and pro-inflammatory mediators under basal and interleukin-1 beta (IL-1β)-stimulated conditions. Cytosolic and nuclear levels of nuclear factor kappa B (NFκB) p50 and p65 subunits in Prg4 (+/+) and Prg4 (-/-) synoviocytes were studied using western blot. Nuclear translocation of p50 and p65 proteins in osteoarthritis (OA) fibroblast-like synoviocytes (FLS) in response to IL-1β stimulation in the absence or presence of rhPRG4 was studied using DNA binding assays. OA synoviocyte (5000 cells per well) proliferation f...
Bioscience Horizons, 2009
Lower back pain (LBP) is a major cause of pain and disability. However, current treatment strategies are focused primarily on relieving its symptoms and have varying degrees of success. For future treatments to be proactive, they must target the underlying pathogenic alterations in cellular biology. Intervertebral disc degeneration (IVDD) has been linked to a high percentage of LBP cases, therefore, inhibition of the processes contributing to IVDD and, regeneration of the intervertebral disc (IVD) matrix lost during IVDD are the primary focuses of current research. Therapies aimed at the inhibition of the cytokine interleukin-1 that is increased during IVDD have been investigated as potential treatments aimed at inhibiting the pathogenic processes of IVDD. In addition, the application of growth factors, such as insulin-like growth factor, transforming growth factor and bone morphogenetic protein or alternatively replacement of abnormal IVD cells, either by injection of mesenchymal stem cells or autologous disc cell transplantation, has been investigated as potential therapeutic agents aimed at regeneration of the IVD matrix. However, for research into these therapeutic techniques to progress, a more detailed knowledge of the complex cellular biology of the IVD is required.
Ageing affects chondroitin sulfates and their synthetic enzymes in the intervertebral disc
Signal Transduction and Targeted Therapy, 2017
The depletion of chondroitin sulfates (CSs) within the intervertebral disc (IVD) during degenerative disc disease (DDD) results in a decrease in tissue hydration, a loss of fluid movement, cell apoptosis, a loss of nerve growth inhibition and ultimately, the loss of disc function. To date, little is known with regards to the structure and content of chondroitin sulfates (CSs) during IVD ageing. The behavior of glycosaminoglycans (GAGs), specifically CSs, as well as xylosyltransferase I (XT-I) and glucuronyltransferase I (GT-I), two key enzymes involved in CS synthesis as a primer of glycosaminoglycan (GAG) chain elongation and GAG synthesis in the nucleus pulposus (NP), respectively, were evaluated in a bovine ageing IVD model. Here, we showed significant changes in the composition of GAGs during the disc ageing process (6-month-old, 2-year-old and 8-year-old IVDs representing the immature to mature skeleton). The CS quantity and composition of annulus fibrosus (AF) and NP were determined. The expression of both XT-I and GT-I was detected using immunohistochemistry. A significant decrease in GAGs was observed during the ageing process. CSs are affected at both the structural and quantitative levels with important changes in sulfation observed upon maturity, which correlated with a decrease in the expression of both XT-I and GT-I. A progressive switch of the sulfation profile was noted in both NP and AF tissues from 6 months to 8 years. These changes give an appreciation of the potential impact of CSs on the disc biology and the development of therapeutic approaches for disc regeneration and repair.
Alterations in ECM signature underscore multiple sub-phenotypes of intervertebral disc degeneration
Matrix biology plus, 2020
The intervertebral disc is a specialized connective tissue critical for absorption of mechanical loads and providing flexibility to the spinal column. The disc ECM is complex and plays a vital role in imparting tissue its biomechanical function. The central NP is primarily composed of large aggregating proteoglycans (PGs) while surrounding AF is composed of fibrillar collagens, I and II. Aggrecan and versican in particular, due to their high concentration of sulfated GAG chains form large aggregates with hyaluronic acid (HA) and provide water binding capacity to the disc. Degradation of aggrecan core protein due to aggrecanase and MMP activity, SNPs that affect number of chondroitin sulfate (CS) substitutions and alteration in enzymes critical in synthesis of CS chains can impair the aggrecan functionality. Similarly, levels of many matrix and matrixrelated molecules e.g. Col2, Col9, HAS2, ccn2 are dysregulated during disc degeneration and genetic animal models have helped establish causative link between their expression and disc health. In the degenerating and herniated discs, increased levels of inflammatory cytokines such as TNF-α, IL-1β and IL-6 are shown to promote matrix degradation through regulating expression and activity of critical proteases and stimulate immune cell activation. Recent studies of different mouse strains have better elucidated the broader impact of spontaneous degeneration on disc matrix homeostasis. SM/J mice showed an increased cell apoptosis, loss of cell phenotype, and cleavage of aggrecan during early stages followed by tissue fibrosis evident by enrichment of several collagens, SLRPs and fibronectin. In summary, while disc degeneration encompasses wide spectrum of degenerative phenotypes extensive matrix degradation and remodeling underscores all of them.