Obesity-induced oleic acid metabolic dysregulation may exacerbate osteoarthritis through the degradation of SOX9.

Obesity-related osteoarthritis (OA) is a degenerative joint disease accompanied by metabolic disorders. However, the specific metabolites and their molecular mechanisms remain unclear. Here, we establish a mouse model of obesity by feeding a high-fat diet (HFD) and find that HFD feeding promotes articular cartilage degeneration and accelerates OA progression. By using the untargeted metabolomics analysis, we identify oleic acid (OLA), a common monounsaturated fatty acid, as a significantly upregulated metabolite accumulating in articular cartilage. We further show that OLA disrupts extracellular matrix (ECM) homeostasis and promotes ubiquitin-mediated degradation of the key upstream transcription factor sex-determining region Y-type high-mobility group box protein 9 (SOX9) in murine chondrocytes and human cartilage explants. RNA-sequencing and further immunofluorescence staining reveal aberrant activation of Ca2+/calmodulin-dependent protein kinase 2 (CaMK2) in the articular cartilage of obese mice. Furthermore, we find that the activation of CaMK2 is induced by OLA, leading to ubiquitin-mediated degradation of SOX9 and subsequent ECM disruption in chondrocytes. Notably, OLA-induced ECM disruption and SOX9 degradation are effectively reversed by a CaMK2 inhibitor. These findings suggest that an OLA-CaMK2-SOX9 molecular axis may be involved in the pathogenesis of obesity-related OA and that CaMK2 could be a potential therapeutic target.