Modulation of phosphate (Pi) and pyrophosphate (PPi) metabolism is critical for development and maintenance of mineralized tissues, including dentin and cementum. Disruption of local Pi/PPi regulators (ANK, PC-1, TNAP) impacts cementogenesis, though dentin formation appears normal, suggesting dentin mineralization is regulated differently than cementum. When factors regulating circulating Pi (FGF-23, PHEX) were disrupted, initial examination indicated that dentin/pulp were affected, while cementum showed minimal disturbance. Based on these data, the following broad hypothesis is set forth: While both cementum and dentin formation are dependent on Pi homeostasis, the genes/proteins controlling formation and regeneration are likely different. We propose that cementogenesis is controlled by ion transporters/local metabolic enzymes including ANK, PC-1, and TNAP, while dentinogenesis is modulated by factors that control levels of circulating Pi, including FGF-23 and PHEX.
Aims :
Aim 1 will determine the role of ANK, PHEX and FGF-23 during cementogenesis versus root dentinogenesis.
Aim 2 will prove that Pi regulation of specific transcription factors controls the cementoblast phenotype.
Aim 3 will prove that increasing local levels of Pi at healing sites using fibrin scaffold delivery systems will promote mineralization. Public Health Relevance: These studies will provide critical information about the genes/factors controlling cementum and dentin formation. Ultimately, the knowledge gained will result in improved therapies for treatment of mineralized tissue disorders and diseases, including dental diseases (caries/periodontal disease), hypophosphatemic conditions, ectopic calcification, and osteoporosis, and in new strategies for regeneration of diseased tissues.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-K (09))
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Wan, Jason
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University of Washington
Schools of Dentistry
United States
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Lau, Wei Ling; Linnes, Michael; Chu, Emily Y et al. (2013) High phosphate feeding promotes mineral and bone abnormalities in mice with chronic kidney disease. Nephrol Dial Transplant 28:62-9
Martins, Luciane; Rodrigues, Thaisangela L; Ribeiro, Mariana Martins et al. (2013) Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype. Bone 56:390-7
Foster, B L; Nagatomo, K J; Tso, H W et al. (2013) Tooth root dentin mineralization defects in a mouse model of hypophosphatasia. J Bone Miner Res 28:271-82
Rodrigues, Thaisângela L; Foster, Brian L; Silverio, Karina G et al. (2012) Correction of hypophosphatasia-associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells. J Periodontol 83:653-63
Gungormus, Mustafa; Oren, Ersin E; Horst, Jeremy A et al. (2012) Cementomimetics-constructing a cementum-like biomineralized microlayer via amelogenin-derived peptides. Int J Oral Sci 4:69-77
Rodrigues, Thaisângela L; Foster, Brian L; Silverio, Karina G et al. (2012) Hypophosphatasia-associated deficiencies in mineralization and gene expression in cultured dental pulp cells obtained from human teeth. J Endod 38:907-12
Silvério, K G; Davidson, K C; James, R G et al. (2012) Wnt/?-catenin pathway regulates bone morphogenetic protein (BMP2)-mediated differentiation of dental follicle cells. J Periodontal Res 47:309-19
Sun, Jian-Xun; Horst, Orapin V; Bumgarner, Roger et al. (2012) Laser capture microdissection enables cellular and molecular studies of tooth root development. Int J Oral Sci 4:7-13
Foster, Brian L; Nagatomo, Kanako J; Nociti Jr, Francisco H et al. (2012) Central role of pyrophosphate in acellular cementum formation. PLoS One 7:e38393
Foster, B L; Nagatomo, K J; Bamashmous, S O et al. (2011) The progressive ankylosis protein regulates cementum apposition and extracellular matrix composition. Cells Tissues Organs 194:382-405

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