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Previous research uncovered the pathogenesis of eye defect and cleft palate of VAD in mice, but the studies on craniofacial skeletal deformity met obstacles, and the cell\/lineage and underlying mechanism remain unclear. The retinoic acid receptor (RAR) is the key transcription factor in retinoid signaling, but individual knockout cannot simulate pathway inhibition. Here, we conditionally expressed dominant-negative RAR\u03b1 mutation ( dnRAR\u03b1) in osteoblasts to specifically inhibit the transcription activity of RAR in mice, which mimics the craniofacial deformities caused by VAD in clinical cases: hypomineralization of cranial bones, mandibular deformity, and clavicular hypoplasia. Furthermore, we performed 3-dimensional reconstruction based on micro\u2013computed tomography and confirmed the abnormalities in the shape, size, and ossification of craniofacial bones due to osteoblastic RAR inhibition. Histological analysis indicated that inhibition of RAR in osteoblasts impaired both bone formation and bone resorption, which was confirmed by transcriptome sequencing of the calvaria. Furthermore, mechanism investigation showed that inhibition of RAR in osteoblasts directly decreased osteoblast differentiation in a cell-autonomous manner by impairing osteogenic gene transcription and also inhibited osteoclast differentiation via osteoblast\u2013osteoclast crosstalk by impairing Rankl transcription. In summary, osteoblastic RAR activity is critical to craniofacial skeletal development, and its dysfunction leads to skeletal deformities mimicking VAD craniofacial defects, providing a new insight for VAD pathogenesis.<\/jats:p>","DOI":"10.1177\/00220345231151691","type":"journal-article","created":{"date-parts":[[2023,4,10]],"date-time":"2023-04-10T07:26:46Z","timestamp":1681111606000},"page":"667-677","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":6,"title":["Osteoblastic RAR Inhibition Causes VAD-Like Craniofacial Skeletal Deformity"],"prefix":"10.1177","volume":"102","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8177-2496","authenticated-orcid":false,"given":"Q.","family":"Dai","sequence":"first","affiliation":[{"name":"The 2nd Dental Center, Shanghai Ninth People\u2019s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China"},{"name":"College of Stomatology, Shanghai Jiao Tong 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