| dc.description.abstract | Dentin and bone are composed of mineralized extracellular matrices (ECM) produced by their formative cells, odontoblasts and osteoblasts. A major component of their ECM is Collage Type 1, along with numerous non-collagenous proteins (NCPs). Dentin sialophosphoprotein (DSPP) is the major NCP of dentin. Belonging to the SIBLING (Small Integrin-binding ligand, N-linked Glycoprotein) family of proteins, DSPP is primarily associated with mineralized tissues. Expression of DSPP (protein and mRNA) has been reported in dentin, periodontium, alveolar bone, condylar cartilage and several non-mineralized tissues. Upon secretion, DSPP is cleaved into two fragments - dentin sialoprotein (DSP) from the N-terminal region and dentin phosphoprotein (DPP) from the C-terminal region. In humans, DSPP mutations have been linked to non-syndromic inherited dentin diseases, dentinogenesis imperfecta (DGI) and dentin dysplasia (DD). DSPP deletion in mice results in formation of hypomineralized dentin. The dentin defects in the Dspp null mice closely resemble the dentin defects of human DGI type III, with widened predentin and irregular dentin mineralization. Although the role of DSPP is critical for the formation of dentin, its role in other hard tissues of the periodontium like alveolar bone and cementum is yet to be studied. Also, previous studies showed that the expression level of DSPP in the rat long bone is approximately 1/400th of that in the rat dentin, however, its role in long bone is not known. This dissertation is a comprehensive effort to outline the function of this protein and its cleaved fragments in periodontium and long bone formation. In the first study, we hypothesized that the proteolytic cleavage of DSPP into its two fragments is essential to periodontal hard tissue formation. Transgenic mice expressing the uncleavable full-length DSPP but lacking endogenous Dspp had severe defects in alveolar bone and cementum. These results indicate that the proteolytic processing of DSPP is crucial for periodontal integrity. Previous studies have demonstrated that the NH2-terminal fragment of DSPP inhibits the formation and mineralization of dentin, while the role of this fragment in periodontium is unclear. In the second study, expressing only the NH2-terminal fragment with the lack endogenous Dspp exacerbated the periodontal defects of Dspp-null mice. This study indicates that the NH2-terminal fragment of DSPP may exert an inhibitory role in the formation and mineralization of hard tissues in the periodontium. Previous reports showed that transgenic expression of DSPP completely rescued the dentin defects of Dmp1-null mice. To investigate if this is true for the long bone defects, we assessed the effects of transgenic DSPP overexpression on osteogenesis by analyzing the formation and mineralization of the long bones in Dmp1-null mice that expresses a transgene encoding full-length DSPP. The transgenic DSPP overexpression partially rescued the long bone phenotypic defects of Dmp1-null mice. Together, these studies shed new light on the significant function of DSPP in mineralized tissue formation. | en |
