Denosumab attenuates knee osteoarthritis progression by inhibiting synovial inflammation via the RANK/TRAF6/FSTL1 signalling
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.
Authors
- Hongtao Tian (ORCID: https://orcid.org/0009-0009-3021-4302)
- Wei Tong (ORCID: https://orcid.org/0000-0001-9951-2273)
- Zhipeng Dai (ORCID: https://orcid.org/0000-0003-3728-5882)
- Yuxiang Hu (ORCID: https://orcid.org/0000-0002-0461-075X)
- Deyao Shi (ORCID: https://orcid.org/0000-0003-4131-1027)
- Zhili He
- Wei Chen (ORCID: https://orcid.org/0000-0001-5451-6430)
- Chaochang Ming
- Yong Liu (ORCID: https://orcid.org/0000-0003-3990-0156)
- Hao Xu (ORCID: https://orcid.org/0000-0003-2809-5243)
- Jian Wang (ORCID: https://orcid.org/0009-0003-8007-5087)
- Weihua Xu (ORCID: https://orcid.org/0000-0003-1510-5625)
- Weijian Liu (ORCID: https://orcid.org/0000-0002-2098-0515)
- Shenghui Lan (ORCID: https://orcid.org/0000-0002-0630-9477)
- Dongdong Xu (ORCID: https://orcid.org/0000-0002-2265-2574)
- Haitao Li (ORCID: https://orcid.org/0000-0001-8431-4098)
- Zengwu Shao
Institutions
- Hebei Medical University (CN)
- Union Hospital (HK)
- Ministry of Education of the People's Republic of China (CN)
- Guiyang Medical University (CN)
- Third Hospital of Hebei Medical University (CN)
- Affiliated Hospital of Guizhou Medical University (CN)
- Wuhan Union Hospital (CN)
- Henan Provincial People's Hospital (CN)
- Shanghai Eighth People Hospital (CN)
- Central Hospital of Wuhan (CN)
- Shanghai Sixth People's Hospital (CN)
- Union Hospital (CN)
- Huazhong University of Science and Technology (CN)
- Henan Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-12-17
- DOI
- https://doi.org/10.1038/s41467-025-66202-z
- Citations
- 1
- Primary Topic
- Osteoarthritis Treatment and Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.67