Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.
Colchicine protects against cartilage degeneration by inhibiting MMP13 expression via PLC-γ1 phosphorylation.
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DOI：
10.1016/j.joca.2021.08.001
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发表时间：
2021-11
影响因子：
7
通讯作者：
Akiyama H
中科院分区：
文献类型：
--
作者：
Takeuchi K;Ogawa H;Kuramitsu N;Akaike K;Goto A;Aoki H;Lassar A;Suehara Y;Hara A;Matsumoto K;Akiyama H
在 mRNA 水平上降低 MMP13 表达的低分子量化合物可能作为缓解骨关节炎 (OA) 疾病的药物 (DMOAD)。本研究的目的是确定一种针对 MMP13 表达的候选 DMOAD。进行高通量筛选以确定抑制炎症细胞因子诱导的 MMP13 表达的化合物。使用基于 iTRAQ 的蛋白质组分析进行独创性途径分析 (IPA)，以确定与细胞因子相关的信号传导途径。通过 RT-qPCR 和蛋白质印迹评估软骨细胞中 MMP13 的表达。此外，对 10 周大的小鼠进行内侧半月板不稳定 (DMM) 手术以诱导 OA，并在术后 12 周处死小鼠进行病理检查。使用 OARSI 评分系统评估 OA。秋水仙碱被确定为 DMOAD 候选药物，因为它在体外抑制炎症细胞因子诱导的 MMP13 表达，并且给予秋水仙碱的 DMM 小鼠具有显着较低的 OARSI 评分（调整后的 P：0.0242，平均差异：1.6，差异的 95% CI：0.1651-3.035），并且显着降低滑膜炎症评分 （调整后的 P：0.0243，平均差异：0.6，差异的 95% CI：0.06158–1.138）高于 DMM 小鼠。 IPA 进一步揭示 Rho 信号通路的组成部分受到细胞因子和秋水仙碱的调节。 IL-1β和TNF-α分别激活RAC1和SRC信号，导致PLC-γ1磷酸化并协同诱导MMP13表达。最值得注意的是，秋水仙碱可消除炎症细胞因子诱导的 PLC-γ1 磷酸化，从而诱导 MMP13 表达。秋水仙碱是一种有前途的候选 DMOAD，它通过破坏 SRC/RAC1-磷酸-PLCγ1-Ca2+ 信号通路来抑制 MMP13 表达和随后的软骨降解。
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. A high-throughput screen was performed to identify compounds that suppress inflammatory cytokine-induced MMP13 expression. Ingenuity pathway analysis (IPA) using iTRAQ-based proteomic analysis was conducted to identify signaling pathways related to cytokines. MMP13 expression in chondrocytes was evaluated by RT-qPCR and western blot. Additionally, 10-week-old mice underwent 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. Colchicine was identified as a DMOAD candidate as it inhibited inflammatory cytokine-induced MMP13 expression in vitro, and the colchicine-administered DMM mice had significantly lower OARSI scores (adjusted P: 0.0242, mean difference: 1.6, 95% 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 DMM mice. 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 PLC-γ1 phosphorylation and synergistic induction of MMP13 expression. Most notably, colchicine abrogates inflammatory cytokine-induced phosphorylation of PLC-γ1, leading to induction of MMP13 expression. Colchicine is a promising candidate DMOAD that inhibits MMP13 expression and consequent cartilage degradation by disrupting the SRC/RAC1-phospho-PLCγ1-Ca2+ signaling pathway.
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影响因子：
4
作者：
Gupta, Shiv K.;Vlahakis, Nicholas E.
通讯作者：
Vlahakis, Nicholas E.
影响因子：
27.4
作者：
Davidson, E. N. Blaney;Vitters, E. L.;van den Berg, W. B.
通讯作者：
van den Berg, W. B.
骨关节炎的炎症。
影响因子：
5.1
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通讯作者：
Otero M
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Long, David L.;Willey, Jeffrey S.;Loeser, Richard F.
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Loeser, Richard F.
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作者：
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