Cherubism and Transforming Growth Factor Beta Signaling

巨颌症是一种罕见的常染色体显性颅面疾病，由SH 3结构域突变引起 结合蛋白2（SH 3BP 2）。这种疾病影响青春期前的儿童，其特征是多房性病变， 下颌骨和/或上颌骨由大量具有破骨细胞样特征的巨大多核细胞组成， 广泛的纤维-骨组织增生。目前，对这种疾病没有公认的治疗方法。 基于长胖症表型的某些特征，我们怀疑增加的TGFβ信号传导 可能在这种疾病的表现中起关键作用，并使用了Sh 3bp 2KI/KI小鼠，一种动物模型 研究这种可能性。 我们的初步研究支持TGFβ信号通路在肿瘤的病因学中起着至关重要的作用。 天真无邪来源于Sh 3bp 2KI/KI的骨髓基质培养物异常显示受损的成骨细胞 分化和稳健的破骨细胞形成。然而，当培养物在存在 TGFβ配体或TGFβ受体1的拮抗剂，成骨细胞分化被拯救，破骨细胞 形成明显减少。此外，血浆中潜伏性TGFβ1的水平比正常人高出近2倍。 Sh 3bp 2KI/KI小鼠与野生型同窝小鼠的比较。基于这些初步数据，我们假设 TGFβ信号水平在长胖症中增加，减少TGFβ信号可能是 有效的治疗方法。 因此，本申请的目标是研究以前未探索的连接 SH 3BP 2和TGFβ信号传导之间的关系。本提案的目的将调查：（1）是否以 TGFβ信号通路是治疗巨颌症的有效方法，（2）TGF β信号通路中的突变如何影响巨颌症的治疗。 SH 3BP 2引起的长胖症导致TGFβ信号转导的改变。从这些研究中获得的信息 将产生重要的信息，治疗和生物学机制的巨像症。

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.