Matrix metalloproteinase and aggrecanase generated aggrecan fragments: implications for the diagnostics and therapeutics of destructive joint diseases

Sumer, E.U.; Qvist, Per; Tankó, László B.

doi:10.1002/ddr.20166

Cited by 10 publications

(8 citation statements)

References 75 publications

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“…MMPs and ADAMTSs serve a key role in the degradation of ECM components, contributing to the destruction of articular cartilage (17). CT treatment has been previously demonstrated to inhibit MMP-13, MMP-3 and ADAMTS4 in a rat OA model (18,19), which was further confirmed in IL-1β-injured chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Calcitonin protects rat chondrocytes from IL‑1β injury via the Wnt/β‑catenin pathway

et al. 2019

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The present study investigated whether the Wnt/β-catenin pathway was involved in the protective effect of calcitonin (CT) in interleukin-1β (IL-1β)-injured rat chondrocytes. Chondrocytes were acquired from the articular cartilage of 4-week-old rats and treated with 10 ng/ml IL-1β to stimulate an in vitro osteoarthritis model. CT (10 and 50 nM) and 5 µm IWR-1-endo (a Wnt/β-catenin inhibitor) was used for treatment. The proliferation and apoptosis of rat articular chondrocytes were measured using a cell counting kit-8 assay and Annexin V/PI staining, respectively. Expression of matrix-metalloproteinases (MMP)-13 MMP3 and MMP9 and aggrecanases [metalloproteinase thrombospondin motifs (ADAMTS4 and ADAMTS5)] were measured to assess the degradation of the cartilage extracellular matrix. The results of the present study demonstrate that CT protected rat chondrocytes from IL-1β stimulation by enhancing cell viability, suppressing apoptosis and decreasing the expression of matrix metallopeptidase (MMP) MMP13, MMP3, MMP9, ADAMTS4 and ADAMTS5. CT treatment also upregulated dickkopf-1 and downregulated β-catenin. IWR-1-endo demonstrated similar effects to that of CT treatment. The administration of CT in addition to IWR-1-endo reinforced the change trends induced by CT or IWR-1-endo in the aforementioned events, indicating that CT possibly acted via the Wnt/β-catenin pathway to exert a protective effect on IL-1β-injured rat chondrocytes.

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Section: Discussionmentioning

confidence: 99%

Calcitonin protects rat chondrocytes from IL‑1β injury via the Wnt/β‑catenin pathway

et al. 2019

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“…Progressive cartilage degradation, the hallmark of OA, results from an imbalance between synthesis and degradation of the extracellular matrix (ECM) proteins by proteases 2 . The inhibition of specific ECM-degrading enzymes is therefore an attractive therapeutic strategy to deliver DMOADs 3 . Type II collagen and aggrecan are two of the major structural components of cartilage, which are degraded by specific matrix metalloproteinases (MMPs) and disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), respectively.…”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

Clément-Lacroix

Little

Smith

et al. 2022

Osteoarthritis and Cartilage

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Objective: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. Methods: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently-labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1a-stimulated glycosaminoglycan release in mouse femoral head cartilage explants, and on interleukin-1bstimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. Results: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC 50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60e>5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 mM and 10 mM, respectively). In DMM mice, GLPG1972/S201086 (30e120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23 e37%), cartilage structural damage (23e39%) and subchondral bone sclerosis (21e36%). In MNX rats, GLPG1972/S201086 (10e50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6 e23%), and decreased proteoglycan loss (~27%) and subchondral bone sclerosis (77e110%). Conclusions: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

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“…In this study, the expression of iNOS and COX2 in mouse chondrocytes treated with IL-1β was upregulated, but this trend was reversed with the addition of curcumin, which is consistent with the literature. MMPs and ADAMTSs serve as key players in the degradation of ECM components, contributing to the destruction of articular cartilage (36). Curcumin treatment has been previously demonstrated to inhibit MMP9 and ADAMTS5 in a rat OA model, which was further confirmed in IL-1βinjured chondrocytes (37).…”

Section: Discussionmentioning

confidence: 79%

Curcumin exerts a protective effect on murine knee chondrocytes treated with IL-1β through blocking the NF-κB/HIF-2α signaling pathway

Wang¹,

Ye²,

Wei³

et al. 2021

Ann Transl Med

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Background: Osteoarthritis (OA) is characterized by erosion and degradation of articular cartilage. This study assessed the effects of curcumin on mouse knee cartilage chondrocytes. Methods: Chondrocytes were treated for 24 hours with interleukin IL-1β (10 ng/mL) alone, or the combination of curcumin (10, 20, and 50 μM) and IL-1β. The proliferation, viability, and cytotoxicity of the chondrocytes were evaluated by the MTS assay. Expression of SOX9, AGG, Col2α, MMP9, ADAMTS5, COX2, iNOS, pIκB-α, pNF-κB, and hypoxia-inducible factor-2α (HIF-2α) were detected by western blotting or quantitative polymerase chain reaction (q-PCR). Nuclear translocation of NF-κB and HIF-2α were investigated by immunofluorescence and immunohistochemistry. In in vivo experiments, mice were subjected to destabilization of the medial meniscus (DMM) and given curcumin orally for 6 weeks. Cartilage integrity was evaluated by OARSI (Osteoarthritic Research Society International) scores. Results: Curcumin significantly inhibited the IL-1β-induced reduction of cell viability, degradation of ECM, and the expression of SOX9, Col2α, and AGG (P<0.01). Western blotting, immunofluorescence and immunohistochemistry experiments demonstrated that curcumin dramatically inhibited the activation of NF-κB/HIF-2α in chondrocytes treated with IL-1β (P<0.01). The articular scores were significantly lower in the DMM-induced OA mice compared to OA mice treated with curcumin (P<0.01). Conclusions: Curcumin may have the potential to inhibit OA development, partly through suppressing the activation of the NF-κB/HIF-2α pathway.

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Matrix metalloproteinase and aggrecanase generated aggrecan fragments: implications for the diagnostics and therapeutics of destructive joint diseases

Cited by 10 publications

References 75 publications

Calcitonin protects rat chondrocytes from IL‑1β injury via the Wnt/β‑catenin pathway

Calcitonin protects rat chondrocytes from IL‑1β injury via the Wnt/β‑catenin pathway

Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5

Curcumin exerts a protective effect on murine knee chondrocytes treated with IL-1β through blocking the NF-κB/HIF-2α signaling pathway

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