Periodontal diseases, among the most prevalent of human chronic diseases, result in marked destruction of soft and hard connective tissues and in tooth loss if left untreated. Recognition that periodontal tissues have the capacity to form new bone and cementum with a functional periodontal ligament (PDL) attachment has resulted in increased efforts focused on understanding the regulators of these tissues. In this regard, we noted a dramatic increase in cementum formation (with normal formation of bone and PDL) and in OPN expression in ank mutant mice when compared with wild-type littermates. ANK is a multipass transmembrane protein, reported to transport intracellular pyrophosphate to the extracellular matrix. ANK mutant mice exhibit generalized progressive arthritis, accompanied by mineral deposition and joint destruction. This data, coupled with the knowledge that mice null for tissue non-specific alkaline phosphatase (TNAP), a PPi-ase enzyme, have limited cementum, the following hypotheses are set forth: 1) Phosphate is a critical modulator of cementoblasts/cementum formation; 2) ANK and TNAP work in concert to regulate the extracellular ratio of PPi to Pi; 3) Expression of OPN is increased in response to increased levels of PPi/Pi, thereby preventing fusion of root with surrounding bone, ankylosis; and 4) Molecules that can regulate phosphate levels at local sites can be used therapeutically in attempts to regenerate mineralized tissues.
Three aims will address these hypotheses.
The first aim will establish the role of ank in modulating genes associated with cementum formation, in situ. Under the second aim the temporal expression of mineral associated genes in cementoblasts exposed to phosphate in vitro will be identified and the phosphate specific promoter regions and transcription factors associated with the OPN promoter determined.
The third aim will prove that modulating the levels of PPi/Pi at sites of periodontal wound healing using a rodent window defect will promote cementum formation. The information gained from these studies is critical for determining the etiology of diseases associated with ectopic calcification and also, will improve the effectiveness of periodontal regenerative therapies (neocementogenesis).
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