FBXO7 protects against osteoarthritis by promoting IL-6 ubiquitination and inhibiting JAK1/STAT3 signaling

Osteoarthritis (OA) is a chronic degenerative disease marked by cartilage destruction and subchondral bone remodeling, resulting in functional disability and pain. FBXO7 has been implicated in various inflammatory conditions; however, its functional and molecular participation in OA development and progression remains largely unexplored. This study investigated FBXO7's protective function in cartilage homeostasis and its underlying molecular mechanisms.

We investigated FBXO7 expression in articular cartilage from OA patients and destabilization of the medial meniscus (DMM)-induced OA mice using transcriptomic analysis, histology, and immunohistochemistry. Functional studies were performed using human chondrocytes and SW-1353 cells to assess the effects of FBXO7 overexpression and knockdown on cell viability, proliferation, senescence, and matrix homeostasis. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteomics, co-immunoprecipitation, and ubiquitination assays were employed to identify FBXO7-interacting proteins and elucidate the underlying molecular mechanisms. In vivo therapeutic efficacy was evaluated using DMM-induced OA mice treated with lenti-FBXO7, and loss-of-function studies were conducted using Fbxo7 conditional knockout mice.

FBXO7 was significantly downregulated in OA patients' cartilage tissues and chondrocytes compared to controls, with clear correlation to cartilage deterioration. FBXO7 overexpression significantly reduced chondrocyte apoptosis and senescence while enhancing proliferation and preserving matrix homeostasis by increasing type II collagen and decreasing MMP13 expression. Mechanistically, we demonstrated that FBXO7 physically interacts with interleukin-6 (IL-6) and functions as an E3 ubiquitin ligase targeting IL-6 for K48-linked ubiquitination specifically at lysine 114. This ubiquitination suppresses IL-6-mediated activation of the JAK1/STAT3 signaling pathway, which is crucial for maintaining cartilage homeostasis. In vivo studies confirmed that FBXO7 overexpression effectively attenuated OA progression, while Fbxo7 conditional knockout mice exhibited accelerated cartilage degradation, enhanced synovial inflammation, and increased cellular senescence.

Our findings establish FBXO7 as a critical regulator of cartilage homeostasis that protects against OA through K48-linked ubiquitination of IL-6 at lysine 114, thereby suppressing the IL-6/JAK1/STAT3 pathway. The identification of this novel FBXO7-IL-6-JAK1/STAT3 axis provides new mechanistic insights into OA pathogenesis and suggests that targeting FBXO7 or its downstream effectors represents a promising therapeutic approach for OA treatment.