MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity

Bollmann, M.; Pinno, K.; Ehnold, L.I.; Märtens, Nicole; Märtson, Aare; Pap, Thomas; Stärke, Christian; Lohmann, Christoph H.; Bertrand, Jessica

doi:10.1016/j.joca.2020.10.009

Cited by 34 publications

(30 citation statements)

References 34 publications

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“…6d). Those results all con rmed that the expression of SDC4 was increased during OA progress, which was consistent with previous studies 24 . We next assessed whether SDC4 had a vital role in cartilage ECM degeneration in vitro and in vivo.…”

Section: Identi Cation Of Sdc4 As the Downstream Molecular Targets Ofsupporting

confidence: 93%

Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting SDC4

Cao

Shi

Zhang

et al. 2021

Preprint

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Emerging evidence suggests that osteoarthritis (OA) is associated with high cholesterol levels. However, the specific mechanism remains unclear. Here, we found that cholesterol metabolism-related gene, LRP3 (low-density lipoprotein receptor-related protein 3) is significantly reduced in high-cholesterol diet mouse’s cartilage. By using global Lrp3−/− mice in vivo and LRP3 lentiviral vector-transduced chondrocytes in vitro, we identified that LRP3 positively regulated chondrocyte extracellular matrix metabolism, and its deficiency aggravated the degeneration of OA cartilage. Regardless of diet, LRP3 overexpression in cartilage attenuated anterior cruciate ligament transection (ACLT)-induced OA progression in rats. Furthermore, LRP3 knockdown upregulated syndecan-4 (SDC4) expression by activating the Ras signaling pathway. We identified SDC4 as a downstream molecular target of LRP3 in OA pathogenesis. Together, these findings suggest that the cholesterol-LRP3-SDC4 axis plays critical roles in the OA development, and the LRP3 gene therapy may provide a new therapeutic regimen for OA treatment.

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Section: Identi Cation Of Sdc4 As the Downstream Molecular Targets Ofsupporting

confidence: 93%

Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting SDC4

Cao

Shi

Zhang

et al. 2021

Preprint

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“…Nevertheless, potential roles of syndecans in chronic conditions have been suggested [14]. Syndecan-4 has been reported to have regulatory role in osteoarthritic cartilage, and syndecan-3 to have proinflammatory effects in joints of arthritic mice [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis

et al. 2021

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The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.

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“…MMP9, also known as gelatinase B, is an enzyme that degrades the ECM components such as collagen, fibronectin, and laminin. MMP9 was found to be upregulated at the mRNA and protein levels in the cartilage and synovial membrane, as well as in the synovial fluid, and was found to be related to the severity of OA (Bollmann et al, 2021). These findings suggest that COL3A1 and MMP9 could be used as OA diagnostic biomarkers.…”

Section: Discussionmentioning

confidence: 78%

COL3A1 and MMP9 Serve as Potential Diagnostic Biomarkers of Osteoarthritis and Are Associated With Immune Cell Infiltration

Wang

Zhang

et al. 2021

Front. Genet.

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BackgroundOsteoarthritis (OA) is one of the most common age-related degenerative diseases. In recent years, some studies have shown that pathological changes in the synovial membrane occur earlier than those in the cartilage in OA. However, the molecular mechanism of synovitis in the pathological process of OA has not been elucidated. This study aimed to identify novel biomarkers associated with OA and to emphasize the role of immune cells in the pathogenesis of OA.MethodsMicroarray datasets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases and were then analyzed using R software. To determine differential immune cell subtype infiltration, the CIBERSORT deconvolution algorithm was used. Quantitative reverse transcription PCR (qRT-PCR) was used to determine the relative expressions of selected genes. Besides, Western blotting was used to assess the protein expression levels in osteoarthritic chondrocytes.ResultsAfter analyzing the database profiles, two potential biomarkers, collagen type 3 alpha 1 chain (COL3A1), and matrix metalloproteinase 9 (MMP9), associated with OA were discovered, which were confirmed by qRT-PCR and Western blotting. Specifically, the results revealed that, as the concentration of IL-1β increased, so did the gene and protein expression levels of COL3A1 and MMP9.ConclusionThe findings provide valuable information and direction for future research into novel targets for OA immunotherapy and diagnosis and aids in the discovery of the underlying biological mechanisms of OA pathogenesis.

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MMP-9 mediated Syndecan-4 shedding correlates with osteoarthritis severity

Cited by 34 publications

References 34 publications

Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting SDC4

Cholesterol-induced LRP3 downregulation promotes cartilage degeneration in osteoarthritis by targeting SDC4

Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis

COL3A1 and MMP9 Serve as Potential Diagnostic Biomarkers of Osteoarthritis and Are Associated With Immune Cell Infiltration

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