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.
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.
|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|
|Verdelis, Kostas; Szabo-Rogers, Heather L; Xu, Yang et al. (2016) Accelerated enamel mineralization in Dspp mutant mice. Matrix Biol 52-54:246-259|
|Jani, Priyam H; Gibson, Monica P; Liu, Chao et al. (2016) Transgenic expression of Dspp partially rescued the long bone defects of Dmp1-null mice. Matrix Biol 52-54:95-112|
|Tian, Ye; Ma, Pan; Liu, Chao et al. (2015) Inactivation of Fam20B in the dental epithelium of mice leads to supernumerary incisors. Eur J Oral Sci 123:396-402|
|Wu, Weijie; Gu, Shuping; Sun, Cheng et al. (2015) Altered FGF Signaling Pathways Impair Cell Proliferation and Elevation of Palate Shelves. PLoS One 10:e0136951|
|Wang, X; Wang, J; Liu, Y et al. (2015) The specific role of FAM20C in dentinogenesis. J Dent Res 94:330-6|
|Mobley, C G; Kuzynski, M; Zhang, H et al. (2015) Dspp-independent Effects of Transgenic Trps1 Overexpression on Dentin Formation. J Dent Res 94:1128-34|
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