Dentin Matrix Protein 1: Effects on Bone Development and Dentin Remineralization

Dentin Matrix Protein 1 (DMP1) is an acidic, hydrophilic protein expressed in all vertebrate hard tissues. The goal of this project is to further investigate the physiologic function of DMP1. The aims of this thesis are: (1) Understand how in vivo bone-specific overexpression of DMP1 during endochondral and intramembranous bone development affects osteogenic protein expression, thereby influencing tissue architecture and mineral density, which ultimately determines the mechanical properties of the bone. (2) Design, produce, and substantiate the efficacy of DMP1-derived biomimetic peptides for dentin remineralization applications that are capable of recapitulating the extracellular matrix functions of endogenous DMP1 during development. To address aim 1, a transgenic mouse overexpressing DMP1 using an osteocalcin promoter (OC-DMP1) was developed to study the effects of DMP1 overexpression during endochonral and intramembranous bone development. We analyzed bone osteogenic expression, architecture and functional properties at 15, 30, 60 and 90 days post-natal and compared them to WT mice of a common background. To address Aim 2, we fabricated peptides derived from DMP1 functional domains. Peptide-A (pA) and peptide-B (pB) contain common collagen-binding domains and unique calcium-binding domains. These peptides were synthesized by solid-phase chemistry. Biomineral nucleating potential of these peptides when coated on native and collagenase-challenged demineralized human dentin was evaluated after exposure to physiological levels of calcium and phosphate. The overarching goal of these works was to further our understanding of DMP1’s functional properties within dental hard tissues. The results of this work provide insights into DMP1’s capacity to affect the biological and structural functions of bone within a mammalian model. DMP1-derived peptides were also shown to have a capacity to remineralize human dentin. Therefore, these findings further our basic science understanding of DMP1’s role in hard tissue development and repair and suggest DMP1 is of importance to the overall field of hard tissue engineering.