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Although genetic mutations for GDD have been identified in the ANO5\/TMEM16E gene, the cellular and molecular mechanisms behind the pathogenesis of GDD remain unclear. Here, we generated the first knock-in mouse model for GDD with the expression of human mutation p.Cys360Tyr in ANO5. Homozygous Ano5 knock-in mice (Ano5KI\/KI) replicated GDD-like skeletal features, including massive jawbones, bowing tibia, bone fragility, sclerosis, and cortical thickening of the femoral and tibial diaphysis. Serum alkaline phosphatase (ALP) levels were elevated in Ano5KI\/KI mice as in GDD patients with p.Cys360Tyr mutation. Calvaria-derived Ano5KI\/KI osteoblast cultures showed increased osteoblastogenesis, including hypermineralized bone matrix and enhanced bone formation-related factors expression. Interestingly, Ano5KI\/KI bone marrow-derived macrophage cultures showed decreased osteoclastogenesis, and Ano5KI\/KI osteoclasts exhibited disrupted actin ring formation, which may be associated with some signaling pathways. In conclusion, this new mouse model may facilitate elucidation of the pathogenesis of GDD and shed more light on its treatment. \u00a9 2021 American Society for Bone and Mineral Research (ASBMR).<\/jats:p>","DOI":"10.1002\/jbmr.4481","type":"journal-article","created":{"date-parts":[[2021,11,29]],"date-time":"2021-11-29T04:24:49Z","timestamp":1638159889000},"page":"515-530","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia"],"prefix":"10.1093","volume":"37","author":[{"given":"Hongyu","family":"Li","sequence":"first","affiliation":[{"name":"Beijing Institute of Dental Research Beijing Stomatological Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Wang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research Beijing Stomatological Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erjun","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Stomatology, Beijing Tongren Hospital Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research Beijing Stomatological Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinrong","family":"Ma","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research Beijing Stomatological Hospital, Capital Medical University Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Miao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Dental Research Beijing Stomatological 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