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Denosumab attenuates knee osteoarthritis progression by inhibiting synovial inflammation via the RANK/TRAF6/FSTL1
Yuxiang Hu1, Wei Chen2,3,4, Shenghui Lan5,6
1Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract:
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.
Insights
Denosumab, a treatment for osteoporosis, effectively reduces synovitis, a key driver of osteoarthritis (OA). This study shows denosumab alleviates OA symptoms and improves joint function in patients.
Area of Science:
- Rheumatology
- Immunology
- Orthopedics
Background:
- Synovitis is a critical early stage in osteoarthritis (OA) development.
- Inhibiting synovitis significantly alleviates OA symptoms and progression.
Purpose of the Study:
- To investigate the effect of denosumab on fibroblast-like synoviocytes (FLSs).
- To evaluate denosumab's efficacy in attenuating synovitis and consequently OA progression.
Main Methods:
- Demonstrated high RANKL expression in OA synovium of mice and patients.
- Administered systemic denosumab in various OA murine and canine models.
- Conducted a single-arm clinical trial assessing VAS, OKS, WOMAC scores, and adverse events.
Main Results:
- Denosumab accumulated in the synovium and reduced synovitis via RANK/TRAF6/FSTL1 signaling.
- Denosumab delayed OA progression in preclinical models.
- Clinical trial showed denosumab alleviated synovitis, pain, and improved joint function in knee OA patients.
Conclusions:
- Denosumab effectively targets synovitis, a key driver of osteoarthritis.
- Findings support denosumab as a potential therapeutic agent for knee OA.
- This study provides a translational basis for clinical application of denosumab in OA treatment.
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