The ubiquitination of IL-6 by FBXO7 mitigates osteoarthritis through JAK1/STAT3 pathway modulation

Osteoarthritis (OA) is a chronic degenerative disease marked by cartilage destruction and subchondral bone remodeling which results in functional disability and pain. FBXO7 has been implicated in various inflammatory conditions, however, very little research has been done to establish its functional and molecular participation in the development and progression of OA. Here we show that the downregulation of FBXO7 may cause the progression and severity of OA. Articular cartilage obtained from OA patients and cartilage excised from DMM-induced OA from mice showed that FBXO7 was downregulated when compared to the controls. Mechanistically, we determined that FBXO7 interacts with the JAK1/STAT3 signaling pathway through IL-6. Immunoprecipitation assay revealed high-affinity physical interactions between FBXO7 and IL-6. When FBXO7 is downregulated in OA, the expression levels of IL-6 are elevated, which increases the activation of the JAK1/STAT3 signaling pathway. This process results in the elevation of MMP13 and suppression of type II collagen, two components crucial in the maintenance of articular cartilage homeostasis. However, overexpression of FBXO7 alleviated cartilage degradation by mediating the ubiquitination of IL-6 and degrading it, which led to the elevated expression of type II collagen, and reversed progression of OA. Therefore, targeting FBXO7 in the treatment of OA presents a promising avenue of therapy.