Cherubism and Transforming Growth Factor Beta Signaling

切尔贝氏症是一种罕见的常染色体显性遗传性颅面部疾病，由SH3区突变引起 结合蛋白2(SH3BP2)。这种疾病影响青春期前儿童，特征是多房性损害 下颌骨和/或上颌骨由许多巨大的多核细胞组成，具有破骨细胞样特征和 广泛的纤维骨性组织增生症。目前，还没有公认的治疗这种疾病的方法。 根据大猩猩表型的某些特征，我们怀疑转化生长因子β信号的增加 可能在这种疾病的表现中起着关键作用，并使用了Sh3bp2KI/Ki小鼠，这是一种动物模型 对于天使主义来说，是为了调查这种可能性。 我们的初步研究支持转化生长因子β信号通路在骨质疏松症发病机制中的重要作用。 小天使主义。Sh3bp2KI/KI来源的骨髓基质细胞异常显示受损的成骨细胞 分化和强健的破骨细胞形成。然而，当文化在存在的情况下生长 拮抗转化生长因子β配体或转化生长因子β受体1，挽救成骨细胞分化和破骨细胞 队形明显减少。此外，血浆中潜伏的转化生长因子β1水平在 Sh3bp2KI/Ki小鼠与野生型窝种的比较。根据这些初步数据，我们假设 转化生长因子β信号转导水平在子痫前期增强，降低转化生长因子β信号转导水平可能是一种 治疗小天使症的有效方法。 因此，本申请的目标是研究以前未探索过的联系 SH3BP2和转化生长因子β信号之间的关系。这项建议的目的将调查：(1)是否针对 转化生长因子β信号通路是治疗母乳症的有效途径； SH3BP2导致母性贫血，导致转化生长因子β信号的改变。从这些研究中获得的信息 将提供有关天使症的治疗方法和生物学机制的重要信息。

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.