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SCP4 represents a novel nucleus\u2010resident phosphatase identified in our previous study. The primary aim of this study was to elucidate the function of SCP4 in the progress of cartilage development and endochondral osteogenesis. <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> and <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>Col2ER<\/jats:italic><\/jats:sup> mice were constructed to assess differences in bone formation using whole skeleton staining. ABH\/OG staining was used to compare chondrocyte differentiation and cartilage development. Relevant biological functions were analysed using RNA\u2010sequencing and GO enrichment, further validated by immunohistochemical staining, Co\u2010IP and Western Blot. Global <jats:italic>SCP4<\/jats:italic> knockout led to abnormal embryonic development in <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>\u2212<\/jats:italic>\/<jats:italic>\u2212<\/jats:italic><\/jats:sup> mice, along with delayed endochondral osteogenesis. In parallel, chondrocyte\u2010specific removal of <jats:italic>SCP4<\/jats:italic> yielded more severe embryonic deformities in <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>Col2ER<\/jats:italic><\/jats:sup> mice, including limb shortening, reduced chondrocyte number in the growth plate, disorganisation and cell enlargement. Moreover, RNA\u2010sequencing analysis showed an association between SCP4 and chondrocyte apoptosis. Notably, Tunnel\u2010positive cells were indeed increased in the growth plates of <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>Col2ER<\/jats:italic><\/jats:sup> mice. The deficiency of SCP4 up\u2010regulated the expression levels of pro\u2010apoptotic proteins both in vivo and in vitro. Additionally, phosphorylation of FoxO3a (pFoxO3a), a substrate of SCP4, was heightened in chondrocytes of <jats:italic>SCP4<\/jats:italic><jats:sup><jats:italic>Col2ER<\/jats:italic><\/jats:sup> mice growth plate, and the direct interaction between SCP4 and pFoxO3a was further validated in chondrocytes. Our findings underscore the critical role of SCP4 in regulating cartilage development and endochondral osteogenesis during embryonic development partially via inhibition of chondrocytes apoptosis regulated by FoxO3a dephosphorylation.<\/jats:p>","DOI":"10.1111\/cpr.13691","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T02:25:24Z","timestamp":1718677524000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Protein phosphatase <scp>SCP4<\/scp> regulates cartilage development and endochondral osteogenesis via <scp>FoxO3a<\/scp> dephosphorylation"],"prefix":"10.1111","volume":"57","author":[{"given":"Pinger","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Orthopedics and Traumatology The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Chinese Medicine  Hangzhou Zhejiang China"},{"name":"The First College of 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