Notch Signaling and Bone Formation

描述(由申请人提供)：对成骨细胞分化的分子机制有一个基本的了解，这对于开发新的骨合成代谢疗法至关重要。生理性Notch信号已成为成骨细胞分化的关键抑制机制，以确保长期维持骨内环境稳定所需的适当的间充质祖细胞。最近发现NOTCH2的过度激活可导致Hajdu-Cheney综合征(HCS)，其特征是儿童骨质疏松、顶骨溶解和蠕虫性骨骼。成骨细胞或破骨细胞缺陷是否是该病的主要原因尚未确定。此外，目前还缺乏治疗这种疾病的有效方法。阐明该病的细胞学基础以及Noch与其他骨生理调节因子之间的关系将为合理设计治疗方法提供依据。在目前的建议中，我们验证了这样的假设，即过度活跃的NOTCH2抑制成骨细胞分化是HCS的主要原因，并且刺激骨合成代谢WNT途径可能减轻与疾病相关的骨缺损。我们进一步研究了Noch和WNT信号之间功能拮抗的生化基础。总体而言，该项目的成功完成有望为HCS的发病机制提供新的机制见解，并可能为该疾病的有效治疗开辟新的途径。

DESCRIPTION (provided by applicant): A fundamental understanding of the molecular mechanism governing osteoblast differentiation is essential for developing novel bone anabolic therapeutics. Physiological Notch signaling has emerged as a critical suppressive mechanism for osteoblast differentiation to ensure a proper pool of mesenchymal progenitors necessary for long-term bone homeostasis. Hyperactivation of NOTCH2 has recently been discover to cause Hajdu-Cheney syndrome (HCS) characterized by childhood osteoporosis, acroosteolysis and wormian bones. Where or not osteoblast or osteoclast defects are the primary cause for the disease has not been established. Moreover, an effective treatment for the disease is currently lacking. Elucidating the cellular basis for the disease and the relationship between NOTCH and other regulators of bone physiology will provide the basis for a rational design of therapeutics. I the current proposal, we test the hypothesis that suppression of osteoblast differentiation by hyperactive NOTCH2 is primarily responsible for HCS, and that stimulation of the bone anabolic WNT pathway may alleviate the bone defects associated with the disease. We further investigate the biochemical basis for the functional antagonism between NOTCH and WNT signaling. Overall, successful completion of this project is expected to provide novel mechanistic insights about the pathogenesis of HCS, and may open new avenues for effective treatments of the disease.