All ETDs from UAB

Advisory Committee Chair

Mary Macdougall

Advisory Committee Members

Selvarangan Ponnazhagan

Dobrawa Napierala

Xu Feng

Rosa Serra

Document Type

Dissertation

Date of Award

2015

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Transforming growth factor-β1 (TGF-β1) is one of the most abundant cytokines of the dentin-pulp complex that regulates a broad range of biological processes related to matrix synthesis and ultimately tooth formation, including secretion and mineralization of the dentin extracellular matrix (DECM). TGF-β1 mediates odontoblast cytodifferentiation from precursor dental pulp cells, being up-regulated in odontoblasts and then incorporated into the DECM as a reservoir that can be utilized in times of mechanical, chemical, or bacterial insult. Formation of the DECM is modulated by the actions of small integrin-binding ligand N-linked glycoproteins (SIBLINGs), which include DMP-1, DSPP, BSP, SPP1, and MEPE, with MEPE being the least characterized member. Critical for phosphate regulation in the skeleton and dentition of mammals, MEPE has elevated expression during matrix mineralization. Transgenic TGFB1 mice displaying the pathophysiology of Camurati-Engelmann disease (CED) demonstrated abnormal molar and incisor development. CED mouse molars displayed more profound defects with decreased mineralization and higher matrix porosity as compared to WT animal teeth. Analysis of CED primary dental pulp cell cultures revealed disrupted expression of TGF-β/BMP signaling pathway and SIBLING genes. In an effort to define the events of tooth formation in which MEPE is critical, molars of Mepe-/- mouse were assessed for DECM density and volume. Interestingly, Mepe-/- mice exhibit increased bone mass with enhanced mineralization activity and increased dentin mineralization. A downstream target of TGF-β1 signaling, MEPE is expressed during tooth formation by odontoblasts and is incorporated into the DECM. Immunohistochemical studies of dental tissues confirmed that MEPE is produced by incisor and molar odontoblasts. These data suggested that MEPE is secreted by mature odontoblasts during dentinogenesis. The molecular crosstalk between TGF-β1 and SIBLING proteins, particularly MEPE, has been observed both in vitro and in vivo, including differentiation of odontoblasts, models of overexpression, and dental and skeletal mineralized tissue pathophysiology. Together, these data demonstrate that TGF-β1 overexpression disrupts DECM formation, and that MEPE inhibits dentin mineralization. However, excessive TGF-β1 levels may be mitigated by SIBLINGs and other TGF-β/BMP family members during tooth development. These studies provide insight into the mineralization defects associated with dentin dysplasia, dentinogenesis imperfecta, hypophosphatemia, and CED.

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