Back to Search
Start Over
Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation
- Source :
- Osteoarthritis Cartilage
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Summary 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-1β and TNF-α activate RAC1 and SRC signals, respectively, leading to the phosphorylation of PLC-γ1 and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, 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-PLCγ1-Ca2+ signaling pathway.
- Subjects :
- Biomedical Engineering
Inflammation
Pharmacology
Article
Chondrocyte
chemistry.chemical_compound
Chondrocytes
Rheumatology
Matrix Metalloproteinase 13
Osteoarthritis
medicine
Animals
Colchicine
Orthopedics and Sports Medicine
RNA, Messenger
Phosphorylation
Phospholipase C gamma
Synovial Membrane
Mice, Inbred C57BL
Blot
medicine.anatomical_structure
chemistry
Synovial membrane
medicine.symptom
Signal transduction
Signal Transduction
Proto-oncogene tyrosine-protein kinase Src
Subjects
Details
- ISSN :
- 10634584
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Osteoarthritis and Cartilage
- Accession number :
- edsair.doi.dedup.....db089a3c3a334c4013012583d978511d