Denosumab attenuates knee osteoarthritis progression by inhibiting synovial inflammation via the RANK/TRAF6/FSTL1 signalling

作者：Yuxiang Hu, Wei Chen, Shenghui Lan, Chaochang Ming, Dongdong Xu, Haitao Li, Hao Xu, Deyao Shi, Weijian Liu, Zhipeng Dai, Jian Wang, Zhili He, Weihua Xu, Zengwu Shao, Yong Liu, Hongtao Tian, Wei Tong · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-66202-z · 被引用次数：6 · 研究领域：Osteoarthritis Treatment and Mechanisms、Bone Metabolism and Diseases、Rheumatoid Arthritis Research and Therapies

Synovitis has recently been shown to be a critical early stage in development of osteoarthritis (OA), and inhibiting synovitis significantly alleviates OA symptoms. Denosumab, a monoclonal antibody targeting RANKL, previously developed for osteoporosis. Here, we report the effect of denosumab on fibroblast-like synoviocytes (FLSs), attenuating synovitis and consequently OA progression. We first demonstrate that RANKL is highly expressed in the knee synovium of OA mice, as well as in patients. Next, we show that denosumab, injected systemically, accumulates in the synovium and effectively reduces synovitis through RANK/TRAF6/FSTL1 signalling in post-traumatic, inflammatory, and aged OA murine models and a beagle dog OA model, delaying OA progression. Finally, a single-arm clinical trial with primary endpoints of VAS and OKS scores, and secondary endpoints of WOMAC score and adverse events rate, shows that denosumab alleviates synovitis and pain, improving joint function in knee OA patients. These findings provide a translational basis for using denosumab to treat knee OA in the clinic. Synovitis is a key early driver of osteoarthritis (OA), and RANKL contributes to cartilage degradation in OA. Here the authors show that denosumab, an anti-RNKL antibody, reduces synovitis and delays OA progression in animal models and patients.