Gnathodiaphyseal dysplasia (GDD) is a rare autosomal dominant genetic disease characterized by the osteosclerosis of tubular bones and the formation of cemento-osseous lesions in mandibles. 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 (Ano5(KI/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 Ano5(KI/KI) mice as in GDD patients with p.Cys360Tyr mutation. Calvaria-derived Ano5(KI/KI) osteoblast cultures showed increased osteoblastogenesis, including hypermineralized bone matrix and enhanced bone formation-related factors expression. Interestingly, Ano5(KI/KI) bone marrow-derived macrophage cultures showed decreased osteoclastogenesis, and Ano5(KI/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. (c) 2021 American Society for Bone and Mineral Research (ASBMR).
基金：
National Natural Science Foundation of China [82071103, 81570958]; Beijing Natural Science Foundation [7162075]; Youjia Biotechnology Ltd, Jilin, China
第一作者机构：[1]Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[1]Capital Med Univ, Beijing Stomatol Hosp, Beijing Inst Dent Res, Beijing, Peoples R China[*1]Capital Med Univ, Beijing Stomatol Hosp, 4 Tiantan West, Beijing 100050, Peoples R China
推荐引用方式(GB/T 7714)：
Li Hongyu,Wang Xiaoyu,Chen Erjun,et al.Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia[J].JOURNAL OF BONE AND MINERAL RESEARCH.2022,37(3):515-530.doi:10.1002/jbmr.4481.
APA：
Li, Hongyu,Wang, Xiaoyu,Chen, Erjun,Liu, Xiu,Ma, Xinrong...&Hu, Ying.(2022).Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia.JOURNAL OF BONE AND MINERAL RESEARCH,37,(3)
MLA：
Li, Hongyu,et al."Introduction of a Cys360Tyr Mutation in ANO5 Creates a Mouse Model for Gnathodiaphyseal Dysplasia".JOURNAL OF BONE AND MINERAL RESEARCH 37..3(2022):515-530
医学