The proper mineralization of bones and teeth has great importance in normal human growth and development and musculoskeletal function. Disruption of normal biomineralization can lead to pathological mineralization or demineralization process. Understanding the complex process of biomineralization relies on knowledge of the structure and function of the organic matrix of mineralized tissues. Acidic phosphoproteins of the organic matrix of bone and dentin have been implicated as regulators of the nucleation process and growth of the inorganic calcium phosphate crystals of bone and teeth in vertebrates. The odontoblasts, which are dentin forming cells are neural crest derived and produce a unique set of phenotypic products. One such protein identified in the dentin matrix is dentin phosphophoryn (DPP). DPP isolated from dentin, has a unique composition with aspartyl and seryl residues comprising at least 75% of the amino acids with 85-90% of the serines being phosphorylated. Until recently, the function of DPP was thought to be structural;however, recent studies have suggested that DPP may have other functions in cell signaling. Therefore, the proposed studies are highly significant as it will provide important mechanistic insights into the function of DPP and its effects on cellular functions and in biological processes such as dentin biomineralization. We hypothesize that DPP is essential for the survival, terminal differentiation of the odontoblasts and in the mineralization of the organic matrix. To test this hypothesis we propose to use molecular approaches to: (a) investigate DPP-mediated adhesive signaling events leading to activation of cell proliferation and survival;(b) identify the mechanism by which DPP activates Smad1 and the downstream transcriptional responses leading to odontoblast terminal differentiation;(c) elucidate the role of DPP in mediating nucleation and growth of hydroxyapatite. Progress in understanding the function of DPP from the perspective of matrix mineralization and signaling has broad ramifications in the field of biomineralization.
During tooth development, the preodontoblasts polarize and elongate as they mature to the secretory form and secrete collagen and a variety of noncollagenous proteins. The major acidic phosphoprotein synthesized by the odontoblasts is dentin phosphophoryn DPP. DPP is a highly acidic protein and has been implicated to function as a regulator of mineral deposition during dentin formation. In this proposal we intend to identify the mechanism by which DPP functions in the extracellular matrix as a regulator of mineralization and intracellularly as a cell signaling molecule. DPP mediated signaling can regulate odontoblast proliferation and differentiation. Results from this study should help us define the various functions of DPP, and its potential use in dentin regeneration.
|Chen, Y; Zhang, Y; Ramachandran, A et al. (2016) DSPP Is Essential for Normal Development of the Dental-Craniofacial Complex. J Dent Res 95:302-10|
|Ravindran, Sriram; George, Anne (2015) Dentin Matrix Proteins in Bone Tissue Engineering. Adv Exp Med Biol 881:129-42|
|Ravindran, Sriram; George, Anne (2014) Multifunctional ECM proteins in bone and teeth. Exp Cell Res 325:148-54|
|Ravindran, Sriram; Zhang, Youbin; Huang, Chun-Chieh et al. (2014) Odontogenic induction of dental stem cells by extracellular matrix-inspired three-dimensional scaffold. Tissue Eng Part A 20:92-102|
|Zhang, Y; Song, Y; Ravindran, S et al. (2014) DSPP contains an IRES element responsible for the translation of dentin phosphophoryn. J Dent Res 93:155-61|
|Ravindran, Sriram; Snee, Preston T; Ramachandran, Amsaveni et al. (2013) Acidic domain in dentin phosphophoryn facilitates cellular uptake: implications in targeted protein delivery. J Biol Chem 288:16098-109|
|Eapen, Asha; Kulkarni, Roma; Ravindran, Sriram et al. (2013) Dentin phosphophoryn activates Smad protein signaling through Ca2+-calmodulin-dependent protein kinase II in undifferentiated mesenchymal cells. J Biol Chem 288:8585-95|
|Opsahl Vital, S; Gaucher, C; Bardet, C et al. (2012) Tooth dentin defects reflect genetic disorders affecting bone mineralization. Bone 50:989-97|
|Eapen, Asha; Ramachandran, Amsaveni; George, Anne (2012) DPP in the matrix mediates cell adhesion but is not restricted to stickiness: a tale of signaling. Cell Adh Migr 6:307-11|
|Eapen, Asha; Ramachandran, Amsaveni; George, Anne (2012) Dentin phosphoprotein (DPP) activates integrin-mediated anchorage-dependent signals in undifferentiated mesenchymal cells. J Biol Chem 287:5211-24|