UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis

Osteoarthritis (OA) is a prevalent and debilitating joint disease in older adults with a complex etiology. We investigated the role of SUMOylation, a post-translational modification, in OA pathogenesis, focusing on the mitochondrial chaperone Prohibitin (PHB1) and the cartilage homeostasis transcription factor PITX1. We hypothesized that oxidative stress-induced SUMOylation promotes PHB1 nuclear accumulation, leading to <i>PITX1</i> downregulation and contributing to OA development. Analysis of cartilage specimens from 27 OA patients and 4 healthy controls revealed an increased nuclear accumulation of PHB1 in OA chondrocytes, accompanied by elevated levels of SUMO-1 and SUMO-2/3. Mechanistically, nuclear PHB1 interacted indirectly with SUMO-1 through a SUMO-interacting motif (SIM), and the deletion of this SIM prevented PHB1 nuclear trapping in OA cells. Furthermore, the SUMO-conjugating enzyme E2 (UBC9) encoded by the <i>UBE2I</i> gene was upregulated in knee OA cartilage, and its overexpression in vitro enhanced PHB1 nuclear accumulation. Consistently, transgenic mice overexpressing the <i>Ube2i</i> gene exhibited increased UBC9 in their knee cartilage, resulting in <i>Pitx1</i> downregulation and the emergence of an early OA-like phenotype in articular chondrocytes. Our findings uncover a novel role for UBC9-mediated SUMOylation in primary knee and hip OA. This pathway enhances PHB1 nuclear accumulation, contributing to <i>PITX1</i> repression and subsequent OA development. These results underscore the importance of SUMOylation in OA pathogenesis and suggest potential molecular targets for early diagnosis and therapeutic intervention.