Tooth development requires the precise spatial and temporal coordination of programs for cell growth, differentiation, and mineralization. In a search for genes required for normal tooth morphogenesis we have studied Dentin matrix protein1 (DMP1), a non- collagenous matrix protein highly expressed in pulp/odontoblast cells, using in vivo loss- and gain-of-function approaches. Dmp1-null mice display profound tooth abnormalities with enlarged pulp chambers, increased width of the predentin zone, hypomineralization, and delayed 3rd molar formation. Realizing that autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to those observed in Dmp1-KO mice, we recently discovered two DMP1 mutations in these patients. We have concluded that these mutations are causes of the phenotypes resembling those of Dmp1-KO mice, although minor differences exist. In a search for mechanisms by which DMP1 controls odontogenesis, we unexpectedly observed a sharp reduction of osterix in the null pulp/odontoblasts. Osterix is a transcriptional factor that is essential for osteogenesis but its role in odontogenesis is unknown. Targeted re-expression of DMP1 in Dmp1-KO pulp/odontoblast cells restores osterix expression and rescues the defects in tooth formation. Notably, we found similar dentin abnormalities in Dmp1-KO, and osterix (conventional or conditional) KO mice. Therefore, we propose that DMP1 mutations are the cause of dentin defects in ARHR patients, and that DMP1 regulates osterix expression at an early stage of tooth development, which plays a critical role for odontogenesis. To test this hypothesis we will study the molecular genetics and pathophysiology of DMP1 mutations through creation of a mouse model with DMP1 mutations. We will also determine the mechanisms by which DMP1 modulates odontogenesis through Osterix via direct action at the nucleus and/or MAPK pathways. The successful completion of these studies will lead to 1) generation of an animal model mimicking these human mutations; 2) understanding the mechanism by which DMP1 controls odontogenesis through osterix via a direct mechanism within the nucleus level and/or MAPK signaling; and 3) identification of bioactive fragment(s) of DMP1 which can ultimately be used in translational applications that will benefit the public by providing therapeutic approaches corresponding to genetic alterations, leading to improved dental/oral health.
Patients with autosomal recessive hypophosphatemic rickets (ARHR) patients manifest phenotypic changes very similar to dentin defects we observed in Dmp1-KO mice. Our discovery of DMP1 mutations in these patients led to the formulation of the current research proposal. Our successful completion of these studies will provide mechanistic details about dentin formation, and will ultimately shed light on the prevention of structural defects in dentin. In addition, the mouse models which to be generated from these studies can be used to correlate individual gene mutations with the appropriate clinical intervention. ? ? ?
|Lv, Kun; Huang, Haiyang; Yi, Xing et al. (2017) A novel auditory ossicles membrane and the development of conductive hearing loss in Dmp1-null mice. Bone 103:39-46|
|Feng, J Q; Zhang, H; Qin, C (2015) Letter to the Editor, ""Osterix Regulates Tooth Root Formation in a Site-specific Manner"". J Dent Res 94:1326|
|Cao, Zhengguo; Liu, Rubing; Zhang, Hua et al. (2015) Osterix controls cementoblast differentiation through downregulation of Wnt-signaling via enhancing DKK1 expression. Int J Biol Sci 11:335-44|
|Hinton, Robert J; Jing, Junjun; Feng, Jian Q (2015) Genetic Influences on Temporomandibular Joint Development and Growth. Curr Top Dev Biol 115:85-109|
|Zhang, Hua; Jiang, Yong; Qin, Chunlin et al. (2015) Essential role of osterix for tooth root but not crown dentin formation. J Bone Miner Res 30:742-6|
|Ren, Yinshi; Han, Xianglong; Ho, Sunita P et al. (2015) Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model. FASEB J 29:2702-11|
|Jing, Junjun; Hinton, Robert J; Mishina, Yuji et al. (2014) Critical role of Bmpr1a in mandibular condyle growth. Connect Tissue Res 55 Suppl 1:73-8|
|Lin, Shu-Xian; Zhang, Qi; Zhang, Hua et al. (2014) Nucleus-targeted Dmp1 transgene fails to rescue dental defects in Dmp1 null mice. Int J Oral Sci 6:133-41|
|Muir, Alison M; Ren, Yinshi; Butz, Delana Hopkins et al. (2014) Induced ablation of Bmp1 and Tll1 produces osteogenesis imperfecta in mice. Hum Mol Genet 23:3085-101|
|Jing, J; Hinton, R J; Jing, Y et al. (2014) Osterix couples chondrogenesis and osteogenesis in post-natal condylar growth. J Dent Res 93:1014-21|
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