The mechanisms that coordinate the shift from joint homeostasis to osteoarthritis (OA) remain unknown. No pharmacological intervention can currently prevent the progression of osteoarthritis. Accumulating evidence has shown that subchondral bone deterioration is a primary trigger for overlying cartilage degeneration. We previously found that H-type vessels modulate aberrant subchondral bone formation during the pathogenesis of OA. However, the mechanism responsible for the elevation of H-type vessels in OA is still unclear. Here, we found that PDGFR-β expression, predominantly in the CD31^hiEmcn^hi endothelium, was substantially elevated in subchondral bones from OA patients and rodent OA models. A mouse model of OA with deletion of PDGFR-β in endothelial cells (ECs) exhibited fewer H-type vessels, ameliorated subchondral bone deterioration and alleviated overlying cartilage degeneration. Endothelial PDGFR-β promotes angiogenesis through the formation of the PDGFR-β/talin1/FAK complex. Notably, endothelium-specific inhibition of PDGFR-β by local injection of AAV9 in subchondral bone effectively attenuated the pathogenesis of OA compared with that of the vehicle-treated controls. Based on the results from this study, targeting PDGFR-β is a novel and promising approach for the prevention or early treatment of OA.

协调从关节稳态转变为骨关节炎 (OA) 的机制仍然未知。目前没有药物干预可以阻止骨关节炎的进展。越来越多的证据表明，软骨下骨退化是上覆软骨退化的主要诱因。我们之前发现 H 型血管在 OA 发病过程中调节异常的软骨下骨形成。然而，OA 中 H 型血管升高的机制仍不清楚。在这里，我们发现 PDGFR-β 表达，主要在 CD31 ^hi Emcn ^hiOA 患者和啮齿动物 OA 模型的软骨下骨内皮细胞显着升高。在内皮细胞 (EC) 中缺失 PDGFR-β 的 OA 小鼠模型表现出较少的 H 型血管，改善了软骨下骨的退化并减轻了覆盖的软骨退化。内皮 PDGFR-β 通过 PDGFR-β/talin1/FAK 复合物的形成促进血管生成。值得注意的是，与载体处理的对照组相比，通过在软骨下骨中局部注射 AAV9 对 PDGFR-β 的内皮特异性抑制有效地减轻了 OA 的发病机制。根据这项研究的结果，靶向 PDGFR-β 是一种新的、有前景的预防或早期治疗 OA 的方法。