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While ROR\u03b2 negatively regulates osteoblast differentiation and contributes to age\u2010related or postmenopausal osteoporosis, its role in early skeletal development remains unclear. This study developed a\n                    <jats:italic>Ror\u03b2<\/jats:italic>\n                    gene knockout (KO) mouse model using CRISPR\/Cas9 to investigate its effects on endochondral ossification. At 4\u2009weeks,\n                    <jats:italic>Ror\u03b2<\/jats:italic>\n                    KO mice exhibited dwarfism and early\u2010onset osteoporosis, with reduced femur length (\u22128.84%), lower cortical and trabecular bone mass, and impaired bone quality. The trabecular bone was fragile, with reduced surface osteoblasts and impaired osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Chondrogenesis was also disrupted, evidenced by a thinner growth plate, fewer chondrocytes, and a disorganized hypertrophic zone (HZ). The expressions of proliferation (Ki67) and hypertrophic differentiation (Collagen X) markers were significantly reduced. Mechanistically, ROR\u03b2 deficiency downregulated hypoxia\u2010inducible factor 1\u2010alpha (HIF\u20101\u03b1) and its downstream target vascular endothelial growth factor A (VEGFA) in both the pre\u2010hypertrophic zone (PHZ) of the growth plate and BMSCs. These findings identify ROR\u03b2 as a critical regulator of endochondral ossification, linking its loss to skeletal defects via impaired HIF\u20101\u03b1\/VEGFA signaling. This study provides insights into potential therapeutic strategies for skeletal diseases such as skeletal dysplasia.\n                  <\/jats:p>","DOI":"10.1096\/fj.202501073rr","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T09:58:49Z","timestamp":1752487129000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["<scp>ROR\u03b2<\/scp>\n                    Deficiency Inhibits Endochondral Ossification in Mice by Mediating the\n                    <scp>HIF<\/scp>\n                    \u20101\u03b1\/\n                    <scp>VEGFA<\/scp>\n                    Signaling Pathway"],"prefix":"10.1096","volume":"39","author":[{"given":"Yifan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Orthodontics, Hospital of Stomatology Jilin University  Changchun China"},{"name":"Department of Dentistry, Orthodontics and Craniofacial Biology, Research Institute for 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