SESN2 drives osteoarthritis progression by inducing MFN2-dependent mitochondrial hyperfusion in rats.

OBJECTIVE

This study aimed to elucidate the role of SESN2 in the pathological process of osteoarthritis (OA), with a particular focus on its potential mechanism in regulating chondrocyte mitochondrial function.

DESIGN

In vitro and in vivo inflammatory models were established using SpragueDawley rats via IL-1β stimulation and surgical destabilization of the medial meniscus (DMM). siRNA, overexpression plasmids, and adeno-associated viruses were used to investigate the role of SESN2 in OA progression, and mechanistic studies were performed to clarify the underlying pathways and downstream targets.

RESULTS

SESN2 expression was significantly upregulated in the chondrocytes and cartilage tissues of OA rats. SESN2 overexpression exacerbated IL-1β-induced chondrocyte inflammation and DMM-induced cartilage damage (OARSI score, 2.000 [95% CI: 0.000-5.000]); conversely, SESN2 knockdown alleviated metabolic disorders and mitochondrial dysfunction in the matrix (Relative ATP content, 0.2639 [95% CI: 0.1068-0.4209]) and ameliorated cartilage degeneration in vivo (OARSI score, -2.000 [95% CI: -5.000 to -1.000]). Mechanistic studies revealed that SESN2 induced mitochondrial hyperfusion in chondrocytes (Mean branch length, 0.4821 [95% CI: 0.2707-0.6935]) and exacerbated mitochondrial dysfunction and inflammation via excessive mitochondrial fusion mediated by MFN2. Further investigation revealed that SESN2 upregulated MFN2 protein expression by promoting its dephosphorylation (Relative protein expression, 0.7693 [95% CI: 0.5392-0.9994]), thereby inducing mitochondrial hyperfusion.

CONCLUSIONS

SESN2 promotes chondrocyte mitochondrial dysfunction and the pathological progression of OA by regulating MFN2 dephosphorylation to induce mitochondrial hyperfusion, thereby providing a new potential target for intervention in OA.