Cherubism and Transforming Growth Factor Beta Signaling

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Cherubism is a rare autosomal dominant craniofacial disorder caused by mutations in SH3-domain binding protein 2 (SH3BP2). This disease affects pre-pubertal children characterized by multilocular lesions in the mandible and/or maxilla consisting of numerous giant multi-nucleated cells with osteoclast like features and extensive fibrous-osseous tissue hyperplasia. Currently, there is no accepted treatment for this disease. Based on certain characteristics of the cherubism phenotype, we suspected that increased TGFβ signaling may have a key role in the presentation of this disease and have used the Sh3bp2KI/KI mice, an animal model for cherubism, to investigate this possibility. Our preliminary studies support a crucial role for the TGFβ signaling pathway in the etiology of cherubism. Bone marrow stromal cultures derived from Sh3bp2KI/KI aberrantly display impaired osteoblast differentiation and robust osteoclast formation. However, when cultures were grown in the presence of antagonists against TGFβ ligands or TGFβ receptor 1, osteoblast differentiation was rescued and osteoclast formation was markedly reduced. Additionally, plasma levels of latent TGFβ1 are nearly 2-fold higher in Sh3bp2KI/KI mice compared to wild type littermates. Based on these preliminary data, we have hypothesized that levels of TGFβ signaling are augmented in cherubism and that reducing TGFβ signaling can be an effective approach to treat cherubism. Therefore, the goals in this application propose to research a previously unexplored connection between SH3BP2 and TGFβ signaling. The aims of this proposal will investigate: (1) whether targeting the TGFβ signaling pathway is an effective therapeutic approach to treat cherubism and (2) how the mutations in SH3BP2 that cause cherubism lead to changes in TGFβ signaling. The information obtained from these studies will yield important information on the therapeutic treatment and biological mechanism of cherubism.