Assessing the function role of sclerostin in periodontal disease in XLH

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Project Summary X-linked hypophosphatemia (XLH) is the most common form of heritable Rickets, characterized clinically by impaired skeletal mineralization and low circulating phosphate levels. XLH is caused by a mutation in the phosphate regulating gene with homology to endopeptidase located on the X chromosome (PHEX) gene, which leads to elevated levels of the phosphotropic hormone, fibroblast growth factor 23 (FGF23), and subsequently renal phosphate wasting. XLH patients also present with a variety of periodontal defects, including aberrant mineralization of both the alveolar bone and cementum, as well as poor periodontal ligament attachment. Although novel treatment strategies have been developed that block FGF23 activity and increase phosphate levels, periodontal disease remains a clinical concern. Our laboratory has recently demonstrated that sclerostin antibody treatment reduces FGF23 and increases circulating phosphate levels. These systemic changes were associated with increased bone mass and mineralization levels in the axial skeleton of Hyp mice. In the current proposal we propose to test the hypothesis that sclerostin is an important mediator of XLH- related periodontal disease and that suppression of sclerostin activity will improve periodontitis. This hypothesis is built on published reports describing the importance of sclerostin and Wnt-signaling in the development of mineralized tissues, including the periodontium. Further, our preliminary data has demonstrated that sclerostin antibody treatment improves alveolar bone mass and periodontal ligament attachment in Hyp mice. To test our hypothesis, we will analyze whether suppressing sclerostin activity via both genetic and pharmaceutical strategies improves the periodontal defects in Hyp mice (Aim 1) and determine the role of sclerostin in the osteogenic differentiation of dental follicle progenitor cells (DFPCs, Aim 2). If successful, the current proposal will further our understanding of the pathophysiology of periodontitis in XLH and provide translational data on the use of a sclerostin antibody, a recently FDA-approved pharmaceutical treatment. Further, the proposal will serve to build the expertise and preliminary data necessary for Dr. Ross to compete for future R01-level funding in dental and craniofacial research.