Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration
Periostin interaction with discoidin domain receptor-1 (DDR1) promotes cartilage degeneration
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DOI：
10.1371/journal.pone.0231501
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发表时间：
2020-04-24
期刊：
影响因子：
3.7
通讯作者：
Attur, Mukundan
中科院分区：
文献类型：
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作者：
Han, Tianzhen;Mignatti, Paolo;Attur, Mukundan
骨关节炎（OA）的特征在于关节软骨的进行性损失，伴随着新骨形成，并且通常是以疼痛、关节功能丧失和残疾为高潮的滑膜增生。然而，OA进展的细胞和分子机制以及软骨、骨和滑膜的相对贡献仍不清楚。我们最近发现，细胞外基质（ECM）蛋白骨膜蛋白（Postn，或成骨细胞特异性因子，OSF-2）在人OA软骨中高水平表达。多个研究组还报告了Postn在几种啮齿动物OA模型中的表达升高。我们以前曾报道，在体外Postn促进胶原蛋白和蛋白多糖降解的人软骨细胞通过AKT/β-连环蛋白信号和下游激活MMP-13和ADAMTS 4的表达。在这里，我们表明，Postn诱导软骨中的胶原和蛋白多糖降解的信号通过盘状结构域受体1（DDR 1），受体酪氨酸激酶。小鼠软骨细胞中DDR 1的遗传缺陷或药理学抑制阻断Postn诱导的MMP-13表达。这些数据表明，虽然DDR 1在机制上参与OA病理生理学，但Postn是信号传导。DDR 1的特异性抑制剂可能为治疗OA提供治疗机会。
Osteoarthritis (OA) is characterized by progressive loss of articular cartilage accompanied by the new bone formation and, often, a synovial proliferation that culminates in pain, loss of joint function, and disability. However, the cellular and molecular mechanisms of OA progression and the relative contributions of cartilage, bone, and synovium remain unclear. We recently found that the extracellular matrix (ECM) protein periostin (Postn, or osteoblast-specific factor, OSF-2) is expressed at high levels in human OA cartilage. Multiple groups have also reported elevated expression of Postn in several rodent models of OA. We have previously reported that in vitro Postn promotes collagen and proteoglycan degradation in human chondrocytes through AKT/beta-catenin signaling and downstream activation of MMP-13 and ADAMTS4 expression. Here we show that Postn induces collagen and proteoglycan degradation in cartilage by signaling through discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase. The genetic deficiency or pharmacological inhibition of DDR1 in mouse chondrocytes blocks Postn-induced MMP-13 expression. These data show that Postn is signaling though DDR1 is mechanistically involved in OA pathophysiology. Specific inhibitors of DDR1 may provide therapeutic opportunities to treat OA.