Osteoarthritis is characterized by the loss of the articular cartilage, bone remodeling, pain, and disability. No pharmacological intervention can currently halt progression of osteoarthritis. Here, we show that blocking receptor tyrosine kinase–like orphan receptor 2 (ROR2) improves cartilage integrity and pain in osteoarthritis models by inhibiting yes-associated protein (YAP) signaling. ROR2 was up-regulated in the cartilage in response to inflammatory cytokines and mechanical stress. The main ligand for ROR2, WNT5A, and the targets YAP and connective tissue growth factor were up-regulated in osteoarthritis in humans. In vitro, ROR2 overexpression inhibited chondrocytic differentiation. Conversely, ROR2 blockade triggered chondrogenic differentiation of C3H10T¹/₂ cells and suppressed the expression of the cartilage-degrading enzymes a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)–4 and ADAMTS-5. The chondrogenic effect of ROR2 blockade in the cartilage was independent of WNT signaling and was mediated by down-regulation of YAP signaling. ROR2 signaling induced G protein and Rho-dependent nuclear accumulation of YAP, and YAP inhibition was required but not sufficient for ROR2 blockade–induced chondrogenesis. ROR2 silencing protected mice from instability-induced osteoarthritis with improved structural outcomes, sustained pain relief, and without apparent side effects or organ toxicity. Last, ROR2 silencing in human articular chondrocytes transplanted in nude mice led to the formation of cartilage organoids with more and better differentiated extracellular matrix, suggesting that the anabolic effect of ROR2 blockade is conserved in humans. Thus, ROR2 blockade is efficacious and well tolerated in preclinical animal models of osteoarthritis.

骨关节炎的特征是关节软骨丧失、骨重塑、疼痛和残疾。目前没有药物干预可以阻止骨关节炎的进展。在这里，我们展示了阻断受体酪氨酸激酶样孤儿受体 2 (ROR2) 通过抑制是相关蛋白 (YAP) 信号传导来改善骨关节炎模型中的软骨完整性和疼痛。响应炎性细胞因子和机械应力，ROR2 在软骨中上调。ROR2、WNT5A 的主要配体以及靶标 YAP 和结缔组织生长因子在人类骨关节炎中上调。在体外，ROR2 过表达抑制软骨细胞分化。相反，ROR2 阻断触发 C3H10T ¹ / _{2的软骨形成分化}并抑制软骨降解酶 a 去整合素和具有血小板反应蛋白基序 (ADAMTS)–4 和 ADAMTS-5 的金属蛋白酶的表达。软骨中 ROR2 阻断的软骨形成作用独立于 WNT 信号传导，并由 YAP 信号传导的下调介导。ROR2 信号传导诱导 G 蛋白和 Rho 依赖性 YAP 核积累，并且需要抑制 YAP，但对于 ROR2 阻断诱导的软骨形成是不够的。ROR2 沉默保护小鼠免受不稳定诱导的骨关节炎的影响，改善了结构结果，持续缓解疼痛，并且没有明显的副作用或器官毒性。最后，在裸鼠移植的人关节软骨细胞中 ROR2 沉默导致形成具有更多和更好分化的细胞外基质的软骨类器官，表明 ROR2 阻断的合成代谢作用在人类中是保守的。因此，ROR2 阻断在骨关节炎的临床前动物模型中是有效的并且耐受性良好。