COUNTERACTING OSTEOARTHRITIS BY ANTI-INFLAMMATORY MACROPHAGE

Osteoarthritis (OA) is a debilitating disorder predominantly affecting the elderly, marked by chronic inflammation, cartilage degradation, and joint impairment. Previous studies have explored the influence of epigenetic factors, particularly the loss of microRNA-29a and changes in histone H3K27me3, on worsening OA via mechanisms such as synovitis, bone degradation, and inhibition of chondrocyte autophagy. Results indicate that the dysregulation of the H3K27me3 demethylase Utx is not only associated with promoted OA severity in humans but also offers protective effects in experimental settings by modulating inflammatory pathways and mitochondrial function. Given the crucial role of macrophages in the pathogenesis of OA, we investigate the relationship between Utx-mediated epigenetic regulation and macrophage functionality. Co-culture models, RNA sequencing, and ChIP sequencing assess the influence of UtxKO macrophages on cartilage matrix metabolism, thus revealing transcriptomic alterations and changes in H3K27me3 binding related to Utx-regulated macrophage activity. Additionally, by employing macrophage-specific Utx knockout (MUtxKO) mice, micro-computed tomography arthrography, serum cytokine arrays, and analyses of human OA tissue seek to ascertain the influence of Utx loss on joint integrity and the concentrations of inflammatory cytokines. Current findings indicate that the absence of Utx in macrophages alters H3K27me3 binding, which subsequently impacts the production of inflammatory cytokines, macrophage polarization, and extracellular vesicles (EVs) formation. MUtxKO mice demonstrate reduced pathology of OA, decreased inflammation, and enhanced biosynthesis EVs derived from MUtxKO macrophages. Furthermore, the extraction of MUtxKO EVs, along with Seahorse flux analysis and microRNA sequencing, while these EVs impacts mitochondrial energy metabolism and extracellular matrix production. Research centered on microRNA interference and mimetics elucidates the particular functions of essential microRNAs in the protective effects mediated by MUtxKO-EVs, while also evaluating the therapeutic potential of administering intra-articular MUtxKO-EVs for the modulation of inflammation and progression of OA. It may be evident that these EVs are involved in regulating glycolysis and mitochondrial energetics, suggesting a novel mechanism through which Utx affects joint health. In light of the research findings, it is observed that Utx loss in macrophages may diminish the methyl histone-binding epigenomic regulation of inflammatory responses, thereby facilitating EVs-mediated restoration of chondrocyte function and hindering the progression of OA. Furthermore, microRNAs derived from MUtxKO-EVs are anticipated to modulate mitochondrial bioenergetics and matrix biosynthesis in chondrocytes. This study emphasizes the potential of targeting Utx or utilizing MUtxKO-EVs as innovative therapeutic strategies for the management of OA