Tooth matrix proteins are tightly regulated and critical for matrix deposition, mineralization and maturation. Altered expression of these proteins leads to enamel and/or dentin defects. We have made the novel observation that macrophage colony stimulating factor (CSF-1), a factor essential for osteoclast-mediated tooth eruption, is also required for normal tooth matrix formation. In op/op mice, a thymidine insertion in the coding sequence of the CSF-1 gene results in a deficiency of both the soluble (s)and membrane bound (m) forms of CSF-1 that decreases osteoclasts and leads to osteopetrosis and failure of tooth eruption. Analysis ofop/op teeth show a combined enamel and dentin defect characterized by thin, poorly organized enamel and dentin dysplasia that was associated with aberrant expression of tooth matrix proteins. Transgenic op/op mice harboring either the sCSF-1 or mCSF-1 cDNAs under the control of the osteocalcin promoter have also been generated and show distinct tooth phenotypes. Expression of sCSF-1 almost corrected the dental defects in op/op mice, while mCSF-1 partially corrected the enamel defect and resulted in an amelogenesis imperfecta phenotype. The long-term goal of this proposal is to determine the role of CSF-1 in primary tooth formation and the mechanisms that mediate the differential effects of CSF-1 isoforms on tooth matrix formation. Our first hypothesis is that CSF-1 is required for normal tooth matrix protein expression and that CSF-1 deficiency causes aberrant expression of these proteins that leads to specific dental defects during development. To address this issue, the expression profile of tooth matrix proteins, histologic features, mineralization and structural integrity by SEM ofop/op teeth will be compared to that of wt during embryonic and postnatal growth. Analysis of the endogenous developmental pattern of sCSF- 1 and mCSF- 1 expression in wt mice using in situ hybridization will be performed to elucidate the potential role of these isoforms in regulating tooth matrix proteins. Our second hypothesis is that sCSF-1 and mCSF-1 differentially regulate tooth matrix protein expression that, in turn, mediate the distinct biologic effects of these isoforms on tooth matrix formation. For these experiments, the patterns of matrix protein expression, mineralization and structural integrity during development will be analyzed in parallel in op/op mice expressing either sCSF-1 or mCSF-1 and correlated with rescue of the tooth phenotype in these mice. We will also test the hypothesis that adenoviral-mediated gene targeting of sCSF-1 to teeth will ameliorate the dental defects in op/op and, perhaps, rescue the enamel defect in mCSF-l-expressing op/op mice. These studies should increase our understanding of the molecular mechanisms involved in sCSF-1 and mCSF-l-mediated tooth matrix formation and may suggest novel therapeutic strategies designed to restore enamel and dentin tissues in a variety of dental disorders including amelogenesis imperfect a and dentinogenesis imperfecta.
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