ReferenceID 4939
Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation
Osteoarthritis Cartilage
OBJECTIVE: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate
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Record Fields
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- Reference Id
- 4939
- Evidence Id
- 21529
- Core Evidence Id
- 21529
- Source Reference Id
- 3137
- Herb2 Reference Id
- HBREF003934
- Subject Paper Key
- HBIN021260_34425229
- Pubmed Id
- 34425229
- Doi
- 10.1016/j.joca.2021.08.001
- Paper Title
- Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation
- Paper Abstract
- OBJECTIVE: Low molecular weight compounds that reduce the expression of MMP13 at the mRNA level might serve as disease-modifying osteoarthritis (OA) drugs (DMOADs). The objective of this study was to identify a candidate DMOAD that targets MMP13 expression. DESIGN: High-throughput screening was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated through RT-qPCR and western blotting analyses. Additionally, 10-week-old mice were subjected to destabilization of the medial meniscus (DMM) surgery to induce OA and were sacrificed 12 weeks post-surgery for pathological examination. OA was evaluated using the OARSI scoring system. RESULTS: Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered mice with DMM presented significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% confidence interval (CI) of difference: 0.1651-3.035) and significantly lower synovial membrane inflammation scores (adjusted P: 0.0243, mean difference: 0.6, 95% CI of difference: 0.06158-1.138) than mice with DMM. IPA further revealed that components of the Rho signaling pathways are regulated by cytokines and colchicine. IL-1beta and TNF-alpha activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-gamma1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-gamma1, leading to the induction of MMP13 expression. CONCLUSIONS: Colchicine is a potential DMOAD candidate that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCgamma1-Ca2+ signaling pathway.
- Journal
- Osteoarthritis Cartilage
- Publish Year
- 2021
- Experiment Subject
- mouse
- Experiment Type
- Animal Experiment
- Phenotype Related
- Osteoarthritis
- Paper Title Cn
- Paper Title En
- Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation
- Bilingual Status
- semi_complete