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Osteocalcin (OCN), a protein abundant in bone matrix, also exhibits high expression in chondrocytes, especially hypertrophic chondrocytes, while its role in endochondral ossification remains unclear. Utilizing a new CRISPR\/Cas9-mediated bglap\u2013bglap2 deficiency (OCNem) mouse model generated in our laboratory, we provide the first evidence of OCN\u2019s regulatory function in chondrocyte differentiation and endochondral ossification. The OCNem mice exhibited significant delays in primary and secondary ossification centers compared to wild-type mice, along with increased cartilage length in growth plates and hypertrophic zones during neonatal and adolescent stages. These anomalies indicated that OCN deficiency disturbed endochondral ossification during embryonic and postnatal periods. Mechanism wise, OCN deficiency was found to increase chondrocyte differentiation and postpone vascularization process. Furthermore, bone marrow mesenchymal stromal cells (BMSCs) from OCNem mice demonstrated an increased capacity for chondrogenic differentiation. Transcriptional network analysis implicated that BMP and TGF-\u03b2 signaling pathways were highly affected in OCNem BMSCs, which is closely associated with cartilage development and maintenance. This elucidation of OCN\u2019s function in chondrocyte differentiation and endochondral ossification contributes to a more comprehensive understanding of its impact on skeletal development and homeostasis.<\/jats:p>","DOI":"10.3390\/ijms25189945","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T01:52:31Z","timestamp":1726624351000},"page":"9945","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Novel Function of Osteocalcin in Chondrocyte Differentiation and Endochondral Ossification Revealed on a CRISPR\/Cas9 bglap\u2013bglap2 Deficiency Mouse Model"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2390-8567","authenticated-orcid":false,"given":"Xiang-Fang","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Shenzhen Children\u2019s Hospital, Shenzhen 518026, China"},{"name":"Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Teng","sequence":"additional","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian V.","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4101-8429","authenticated-orcid":false,"given":"Zhe","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Endocrinology, Shenzhen Children\u2019s Hospital, Shenzhen 518026, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6477-9055","authenticated-orcid":false,"given":"Pei-Gen","family":"Ren","sequence":"additional","affiliation":[{"name":"Shenzhen College of Advanced Technology, University of Chinese Academy of Sciences, Shenzhen 518055, China"},{"name":"Center for Cancer Immunology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000328081","article-title":"Chondrocyte proliferation and differentiation","volume":"21","author":"Wuelling","year":"2011","journal-title":"Endocr. 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