title: Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome.
abstract: The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation.
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Han
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Haochen
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.|Oral Biology Curriculum, School of Density, University of North Carolina at Chapel Hill, The United States.
authors.forename: Sing-Wai
authors.initials: SW
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Zhengyi
authors.initials: Z
authors.lastname: Cao
authors.affiliation: School of Physics and Electronic Information, Henan Polytechnic University, Jiaozuo, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, China.|National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, The United States.
authors.forename: Tao
authors.initials: T
authors.lastname: Cai
authors.affiliation: Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Yixiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Prosthodontics, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Hailan
authors.initials: H
authors.lastname: Feng
mesh_terms: D000328:Adult; D016301:Alveolar Bone Loss / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015415:Biomarkers; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003744:Dental Enamel Hypoplasia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006201:Hair Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010012:Osteogenesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors