The soluble (s) and membrane-bound (m) forms of CSF-1 are synthesized by odontoblasts. Our recent studies show that CSF-1 deficient op/op mice expressing mCSF-1 in teeth under the control of the osteocalcin promoter show an amelogenesis imperfecta phenotype, while op/op mice expressing sCSF-1 show a more normal phenotype with chalky white teeth. In these mice, dentin morphology by SEM is similar to wt. Objective: To determine the in vivo biologic effect of mCSF-1 and sCSF-1, selectively expressed in a CSF-1 deficient background, on enamel matrix protein gene expression. Methods: Mandibles were dissected from 7 wk mCSF-1 op/op, sCSF-1 op/op and wt mice. Total RNA, isolated from teeth using RNA STAT-60 (TEL-TEST, Inc.), was converted to cDNA with TaqMan kit (ABI), and analyzed for tooth matrix protein transcripts using QRT-PCR. Data was normalized to cyclophilin-A levels. Results: The osteocalcin promoter targets odontoblasts and high CSF-1 protein levels were detected in teeth of mCSF-1 and sCSF-1 op/op mice. Compared to wt, enamel-enriched matrix proteins were down-regulated by mCSF-1 and up-regulated by sCSF-1. Teeth from mCSF-1op/op mice showed a marked decrease in ENAM, AMBN and EMSP1 compared to wt. In contrast, sCSF-1 op/op teeth showed an increase in these matrix proteins with EMSP1 and ENAM ranging from 3- to 8-fold higher than wt levels. Conclusion: These findings indicate that mCSF-1 and sCSF-1 differentially regulate enamel matrix proteins that, in turn, may contribute to the distinct tooth phenotypes observed in op/op mice expressing each isoform. Results: suggest that the relative ratio of the soluble and membrane bound forms of CSF-1 in the tooth microenvironment may be critical for normal enamel matrix protein expression. Targeting a specific CSF-1 isoform to teeth may provide a novel strategy for regulating enamel matrix proteins in dental disorders such as amelogenesis imperfecta. Supported by grants AR42306, DE13221, & DE09875.

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