Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China; The First People's Hospital of Zhaoqing, Zhaoqing 526020, China.
Guangxi Key Laboratory of basic and translational research of Bone and Joint Degenerative Diseases, Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
Int Immunopharmacol. 2022 Nov;112:109225. doi: 10.1016/j.intimp.2022.109225. Epub 2022 Sep 9.
Osteoarthritis (OA) is the most prevalent degenerative whole-joint disease characterized by cartilage degeneration, synovial hyperplasia, osteophyte formation, and subchondral bone sclerosis. Currently there are no disease-modifying treatments available for OA because its etiology and pathogenesis are largely unknown. Here we report that a natural carboxylic polyether ionophore that is used as an anti-tumor drug, salinomycin (SAL), may be a promising therapeutic drug for OA in the future. We found that SAL showed no cytotoxicity on mouse chondrocytes and displayed a protective effect against interleukin-1β (IL-1β), in cultured mouse chondrocytes and cartilage explants. Treatment with low SAL concentrations directly upregulated the anabolism factors collagen II and aggrecan, while it inhibited the catabolic factors matrix metalloproteinase-13 (MMP13) and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) to protect against extracellular matrix (ECM) degradation, and also suppressed inflammatory responses in mouse chondrocytes. Furthermore, SAL reduced the severity of OA-associated changes and delayed cartilage destruction, subchondral bone sclerosis, and osteophyte formation in a destabilized medial meniscus (DMM) surgery-induced mouse OA model. Mechanistically, a low SAL concentration induced anabolism and inhibited catabolism in chondrocytes via inhibiting Lrp6 phosphorylation and Wnt/β-catenin signaling. Our results suggested that SAL may serve as a potential disease-modifying therapeutic against OA pathogenesis.
骨关节炎（OA）是最常见的退行性全关节疾病，其特征为软骨退化、滑膜增生、骨赘形成和软骨下骨硬化。目前尚无针对 OA 的疾病修正治疗方法，因为其病因和发病机制在很大程度上尚不清楚。在这里，我们报告称，一种天然羧酸聚醚离子载体，被用作抗肿瘤药物的萨立霉素（SAL），将来可能成为 OA 的一种有前途的治疗药物。我们发现 SAL 对小鼠软骨细胞没有细胞毒性，并且在培养的小鼠软骨细胞和软骨外植体中显示出对白细胞介素 1β（IL-1β）的保护作用。低浓度的 SAL 直接上调了合成代谢因子胶原 II 和聚集蛋白聚糖，同时抑制了分解代谢因子基质金属蛋白酶 13（MMP13）和含血栓反应蛋白基序的金属蛋白酶 5（ADAMTS5），从而防止细胞外基质（ECM）降解，并抑制了小鼠软骨细胞的炎症反应。此外，SAL 减少了与 OA 相关的变化的严重程度，并延迟了不稳定内侧半月板（DMM）手术诱导的小鼠 OA 模型中的软骨破坏、软骨下骨硬化和骨赘形成。从机制上讲，低浓度的 SAL 通过抑制 Lrp6 磷酸化和 Wnt/β-catenin 信号通路，在软骨细胞中诱导合成代谢并抑制分解代谢。我们的结果表明，SAL 可能成为治疗 OA 发病机制的一种有潜力的疾病修正治疗药物。
