This research proposal focuses on the biological roles of FAM20C (also known as Dentin Matrix Protein 4, DMP4) in the formation of dentin, cementum, enamel and bone. Our recent studies have established that this novel molecule plays crucial roles in odontogenesis and osteogenesis. We have discovered that the inactivation of Fam20C in mice leads to: 1) significant defects in the dentin, cementum, enamel and bone; 2) a decreased serum level of phosphorus in contrast to an elevated serum level of fibroblast growth factor 23 (FGF23); 3) loss of normal morphology of odontoblasts and ameloblasts; and 4) reduced expression of the differentiation markers for odontoblasts and osteoblasts [including dentin matrix protein 1 (DMP1), a differentiation/mineralization marker]. In vitro studies revealed that recombinant FAM20C promotes the differentiation of preosteoblasts and increases the expression of DMP1, while shRNA knockdown of FAM20C leads to a remarkable reduction of DMP1 and elevation of FGF23 in multiple osteogenic cell lines. Our preliminary data led us to believe that the inactivation of Fam20C prevents cells from differentiating into mature odontogenic/osteogenic cells and leads to hypophosphatemia. The combined results of cell differentiation failure and lower serum phosphate level cause defects in the teeth and bones of Fam20C-deficient mice. The following three Specific Aims are proposed to test the central hypothesis that FAM20C promotes the differentiation of cells forming mineralized tissues and regulates phosphate homeostasis via the mediation of FGF23: (1) To evaluate the molecular pathogenesis of FAM20C-associated disorders in mice and humans by analyzing the specific effects of FAM20C inactivation on odontoblasts, cementoblasts, osteoblasts and ameloblasts, and by examining whether the expression of a normal human FAM20C transgene can rescue the mouse Fam20C-deficient defects and if expressing a mutant mouse Fam20C transgene mimicking a human FAM20C mutation can recapitulate the phenotype identified in some human patients; (2) To determine if FAM20C is involved in biomineralization via the FGF23-mediated regulation of phosphate homeostasis by analyzing double Fam20C- and Fgf23-null mice, injecting anti-FGF23 antibodies and administering a high-phosphate diet in the Fam20C-deficient mice; and (3) To determine if FAM20C regulates DMP1 in dentinogenesis and osteogenesis by examining if expressing the Dmp1 transgene can rescue the dentin and bone defects in the Fam20C-deficient mice, and by analyzing the in vitro effects of adding or expressing DMP1 on Fam20C-deficient cell lines. The proposed studies, which are a necessary step in understanding how FAM20C functions in odontogenesis and osteogenesis, will contribute new insights into the molecular basis for genetic and metabolic disorders that affect the craniofacial complex and the axial skeleton.

Public Health Relevance

Our recent studies showed that inactivation of FAM20C (DMP4) leads to defects in the dentin, enamel and bone; these defects resemble the human diseases, dentinogenesis imperfecta, amelogenesis imperfecta and rickets, respectively. The proposed studies aimed at gaining fundamental information about how FAM20C functions will unfold greater understanding of the mechanisms controlling biomineralization process, and a better understanding of this process is necessary, not only to understand the normal development of the mineralized tissues, but also to eventually deliver better therapeutic strategies for the hard tissue diseases.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Wan, Jason
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Texas A&M University
Other Basic Sciences
Schools of Dentistry/Oral Hygn
College Station
United States
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Zhang, Hua; Xie, Xiaohua; Liu, Peihong et al. (2018) Transgenic expression of dentin phosphoprotein (DPP) partially rescued the dentin defects of DSPP-null mice. PLoS One 13:e0195854
Liu, Xuenan; Li, Nan; Zhang, Hua et al. (2018) Inactivation of Fam20b in the neural crest-derived mesenchyme of mouse causes multiple craniofacial defects. Eur J Oral Sci 126:433-436
Jiang, Chengyu; Zurick, Kevin; Qin, Chunlin et al. (2018) Probing the influence of SIBLING proteins on collagen-I fibrillogenesis and denaturation. Connect Tissue Res 59:274-286
Liu, Chao; Zhang, Hua; Jani, Priyam et al. (2018) FAM20C regulates osteoblast behaviors and intracellular signaling pathways in a cell-autonomous manner. J Cell Physiol 233:3476-3486
Jani, Priyam; Liu, Chao; Zhang, Hua et al. (2018) The role of bone morphogenetic proteins 2 and 4 in mouse dentinogenesis. Arch Oral Biol 90:33-39
Liu, Chao; Zhou, Nan; Wang, Yu et al. (2018) Abrogation of Fam20c altered cell behaviors and BMP signaling of immortalized dental mesenchymal cells. Exp Cell Res 363:188-195
Liu, Peihong; Ma, Su; Zhang, Hua et al. (2017) Specific ablation of mouse Fam20C in cells expressing type I collagen leads to skeletal defects and hypophosphatemia. Sci Rep 7:3590
Zhang, Hua; Jani, Priyam; Liang, Tian et al. (2017) Inactivation of bone morphogenetic protein 1 (Bmp1) and tolloid-like 1 (Tll1) in cells expressing type I collagen leads to dental and periodontal defects in mice. J Mol Histol 48:83-98
Xie, Xiaohua; Liu, Chao; Zhang, Hua et al. (2016) Abrogation of epithelial BMP2 and BMP4 causes Amelogenesis Imperfecta by reducing MMP20 and KLK4 expression. Sci Rep 6:25364
Zhang, H; Liu, P; Wang, S et al. (2016) Transgenic expression of dentin phosphoprotein inhibits skeletal development. Eur J Histochem 60:2587

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