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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 PITX1 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 UBE2I gene was upregulated in knee OA cartilage, and its overexpression in vitro enhanced PHB1 nuclear accumulation. Consistently, transgenic mice overexpressing the Ube2i gene exhibited increased UBC9 in their knee cartilage, resulting in Pitx1 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 PITX1 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.<\/jats:p>","DOI":"10.3390\/ijms26136281","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T06:56:54Z","timestamp":1751353014000},"page":"6281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["UBC9-Mediated SUMO Pathway Drives Prohibitin-1 Nuclear Accumulation and PITX1 Repression in Primary Osteoarthritis"],"prefix":"10.3390","volume":"26","author":[{"given":"Roxanne","family":"Doucet","sequence":"first","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Program of Molecular Biology, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdellatif","family":"Elseoudi","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bita","family":"Rostami-Afshari","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3301-069X","authenticated-orcid":false,"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Biochemistry Division, Chemistry Department, Faculty of Science, Tanta University, Tanta 31527, Gharbia Governorate, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Taheri","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Pellicelli","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Picard","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Lavoie","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Da Shen","family":"Wang","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Lavigne","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Orthopedic Division, Maisonneuve-Rosemont Hospital, Montreal, QC H1T 2M4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen F.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3577-3551","authenticated-orcid":false,"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[{"name":"Viscogliosi Laboratory in Molecular Genetics of Musculoskeletal Diseases, Azrieli Research Center, CHU Sainte-Justine, Montreal, QC H3T 1C5, Canada"},{"name":"Program of Molecular Biology, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"},{"name":"Department of Stomatology, Faculty of Dentistry, Universit\u00e9 de Montr\u00e9al, Montreal, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41572-025-00594-6","article-title":"Osteoarthritis","volume":"11","author":"Tang","year":"2025","journal-title":"Nat. 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