Department of Orthopaedics, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Int Immunopharmacol. 2023 Aug;121:110433. doi: 10.1016/j.intimp.2023.110433. Epub 2023 Jun 19.
Osteoarthritis (OA) is a chronic joint disorder with a serious impact on society. The main pathological change in OA is articular cartilage degeneration, which is directly associated with imbalance of anabolic and catabolic activities in chondrocytes.
To evaluate the expression and biological effects of ROR1 in OA cartilage and determine whether knockdown of ROR1 attenuates cartilage degeneration.
ROR1 expression in OA clinical specimens was evaluated by western blotting and immunohistochemistry. The effects of ROR1 on anabolic and catabolic activities were evaluated in Wnt5a-treated human primary chondrocytes by western blotting, immunofluorescence, and luciferase assay. The effects of ROR1 knockdown on cartilage degeneration in a surgical OA mouse model were examined by X-ray imaging and Safranin O-Fast Green histological staining.
ROR1 was considerably upregulated in cartilage tissues of OA patients. ROR1 knockdown alleviated the activation of the NF-κB signaling pathway and reversed the suppression of collagen II and aggrecan by Wnt5a, as well as upregulation of ADAMTS-5 and MMP-13 in chondrocytes. In addition, ROR1 knockdown significantly reduced Wnt5a-induced STAT3 nuclear translocation. STAT3 binding to the ROR1 promoter indicated a positive feedback loop between ROR1 and STAT3. ROR1 knockdown was confirmed to dramatically alleviate cartilage degradation in the DMM induced-OA mouse model.
Increased expression of ROR1 in OA cartilage tissues leads to a positive feedback loop with STAT3, which activates the NF-κB signaling pathway, resulting in an imbalance between chondrocyte anabolism and catabolism. These results indicate a potential new therapeutic target for the treatment of OA.
骨关节炎（OA）是一种慢性关节疾病，对社会有严重影响。OA 的主要病理变化是关节软骨退化，这与软骨细胞合成代谢和分解代谢活动的失衡直接相关。
评估 ROR1 在 OA 软骨中的表达和生物学效应，并确定敲低 ROR1 是否能减轻软骨退变。
通过 Western blot 和免疫组织化学评估 OA 临床标本中 ROR1 的表达。通过 Western blot、免疫荧光和荧光素酶测定评估 Wnt5a 处理的人原代软骨细胞中 ROR1 对合成代谢和分解代谢活性的影响。通过 X 射线成像和番红 O-fast 绿组织染色检查 ROR1 敲低对手术 OA 小鼠模型中软骨退变的影响。
ROR1 在 OA 患者的软骨组织中显著上调。ROR1 敲低减轻了 NF-κB 信号通路的激活，并逆转了 Wnt5a 对胶原 II 和聚集蛋白聚糖的抑制以及软骨细胞中 ADAMTS-5 和 MMP-13 的上调。此外，ROR1 敲低显著减少了 Wnt5a 诱导的 STAT3 核转位。STAT3 与 ROR1 启动子的结合表明 ROR1 和 STAT3 之间存在正反馈回路。ROR1 敲低被证实可显著减轻 DMM 诱导的 OA 小鼠模型中的软骨降解。
OA 软骨组织中 ROR1 的表达增加导致与 STAT3 的正反馈循环，激活 NF-κB 信号通路，导致软骨细胞合成代谢和分解代谢失衡。这些结果表明 ROR1 可能成为 OA 治疗的新靶点。
