Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, NYU Langone Orthopedic Hospital, New York, NY, United States of America.
PLoS One. 2020 Apr 24;15(4):e0231501. doi: 10.1371/journal.pone.0231501. eCollection 2020.
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/β-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.
骨关节炎（OA）的特征是进行性关节软骨丧失，伴有新骨形成，通常还有滑膜增生，最终导致疼痛、关节功能丧失和残疾。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 软骨中高表达。多个小组还报告了几种 OA 啮齿动物模型中 Postn 的表达升高。我们之前曾报道过，在体外，Postn 通过 AKT/β-连环蛋白信号通路和下游 MMP-13 和 ADAMTS4 表达的激活，促进人软骨细胞中胶原和蛋白聚糖的降解。在这里，我们表明 Postn 通过 discoidin 结构域受体-1（DDR1）信号通路诱导软骨中胶原和蛋白聚糖的降解，DDR1 是一种受体酪氨酸激酶。在小鼠软骨细胞中，DDR1 的基因缺失或药理学抑制阻断了 Postn 诱导的 MMP-13 表达。这些数据表明，Postn 通过 DDR1 信号通路在 OA 病理生理学中具有机制作用。DDR1 的特异性抑制剂可能为治疗 OA 提供治疗机会。
