The inorganic phase in bone and dentin contribute to the unique, compressive strength of these tissues. The extracellular organic phase dictates the deposition of calcium and phosphate mineral to form oriented hydroxyapatite crystals. This process is facilitated with the aid of acidic, noncollagenous proteins like dentin matrix protein 1 (DMP1). While DMP1 is known to participate as a regulatory component in the highly complex process of biomineralization in teeth and bones, its therapeutic potential and mechanism of action is not yet known. This project proposes to use two transgenic, gain-of-function models for analyzing bone and tooth biochemistry, architecture, and mechanical properties. The mouse models are designed using the osteocalcin (OC) and dentin sialophosphoprotein (DSPP) gene promoters to drive tissue-specific overexpression in bone and teeth, respectively. The overall goal of this research is to characterize how tissue- specific DMP1 overexpression alters tissue biochemistry and architecture in order to determine how increased levels of DMP1 influence their mechanical properties. The central hypothesis is that overexpression of DMP1 will modulate the extracellular architecture, increase mineral density, and thereby improve the mechanical properties of bone and dentin in transgenic mice compared to wild type. The proposed aims will determine the temporal expression of osteogenic and odontogenic genes, while also analyzing the spatio-temporal production of key proteins involved in mineralization. The architecture of bone and tooth ECM will be characterized via micro-CT analysis. Mineral density will be quantified using backscatter scanning electron microscopy. Micro and nano-scale mechanical properties will be determined using three-point bend testing and nano-indentation. These data will be statistically analyzed to determine the effect of tissue-specific DMP1 overexpression on progenitor cell differentiation and its influence on tissue mechanical properties. This knowledge would greatly assist in developing novel, tissue engineered therapies for pathological conditions of dental and craniofacial tissues.
Unsuccessful mineralization during hard tissue development, remodeling, or regeneration is central to many pathological conditions such as odontogenesis imperfecta types II and III, osteoporosis, conductive hearing loss, and hypophosphatemic rickets. This study aims to evaluate the affect of tissue-specific DMP1 overexpression in bone and teeth. We will gain insight into how increased expression of DMP1 alters tissue biochemistry, architecture, and ultimately, mechanical properties. This knowledge will bring us closer to the development of more effective treatment methods for patients suffering from these diseases.
|Padovano, J D; Ravindran, S; Snee, P T et al. (2015) DMP1-derived peptides promote remineralization of human dentin. J Dent Res 94:608-14|
|Padovano, Joshua D; Ramachandran, Amsaveni; Bahmanyar, Sara et al. (2014) Bone-specific overexpression of DMP1 influences osteogenic gene expression during endochondral and intramembranous ossification. Connect Tissue Res 55 Suppl 1:121-4|