MECHANISMS OF INHIBITING BONE FORMATION THROUGH ANTAGONISM

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DESCRIPTION (provided by applicant): An important area of research is the identification and characterization of key molecules and pathways that promote bone formation, de novo. Currently the most promising anabolic agent used for the systemic treatment of osteoporosis is parathyroid hormone (PTH) and recently it has been shown that sclerostin (sost), a negative regulator of bone formation, is a direct target of PTH, suggesting that sost regulation may play an important role in PTH-dependent bone formation. This is of great biomedical importance since loss of Sost in humans causes two severe bone dysplasias: sclerosteosis (MIM 269500) and Van Buchem (VB) disease (MIM 239100), both characterized by hyperostosis and thus positioning sost as an ideal new target for the treatment of bone loss. We have recently shown that over-expressing human Sost in transgenic mice results in osteopenia, while mice expressing a transgene that mimics the VB allele, are unaffected. Through a combination of cross-species sequence comparisons followed by in vitro and in vivo enhancer assays, we have identified a highly-conserved element, ECR5 that functions as an osteoblast/osteocyte enhancer in vitro and in vivo. Further, we have shown in vitro that ECR5 is PTH-responsive, and that PTH- mediated suppression of sost requires the ECR5 distal enhancer, independently of the proximal sost promoter. Since modulating expression of proteins that regulate bone formation is of great biomedical importance and because of the well-documented role of sost in regulating osteoblast activity and bone formation, the overarching goal of our research is to understand the hormonal regulation and signal transduction pathways involving negative regulators of bone formation or `bone- antagonists'. In particular, we are interested in elucidating the transcriptional mechanisms by which sost expression is modulated during osteogenesis, bone patterning, and bone metabolism. We hypothesize that this antagonist is under tight transcriptional control from several signaling pathways known to be critical during bone homeostasis, such as the PTH- and BMP- signaling, and is preferentially up-regulated or down-regulated as needed by members of the Myocyte Enhancer Factor 2 (Mef2) family to mediate its effector function via fine-tuning of its transcript levels.