mTOR SIGNALING: A NOVEL MECHANISM OF WNT'S ANABOLIC EFFECTS ON BONE

描述(申请人提供)：骨质疏松症是一个主要的公共健康问题，其特征是骨量和骨密度降低。WNT信号促进出生后骨量增加。我们的长期目标是阐明Wnt信号通路对骨的合成代谢作用的分子机制。我们假设，在成骨细胞中，1)Wnt信号调节mTOR(雷帕霉素靶标的哺乳动物同源)活性，mTOR是一种重要的丝氨酸/苏氨酸激酶，在调节蛋白质合成和细胞生长方面发挥核心作用；2)mTOR在介导Wnt对骨骼的合成代谢作用中发挥关键作用。这些假说基于：1)我们的生化分析表明，Wnt信号通路在体内和体外都调节非成骨细胞中mTOR的活性；以及2)常染色体显性遗传性高骨量疾病(HBM)和结节硬化性骨发育不良(TSC)都以骨骼和颅面部骨骼的成骨细胞和骨硬化性改变为特征，因此都被归类为硬化性骨发育不良；在这两种疾病中，Wnt的高活性和mTOR信号分别参与了这两种疾病的研究。这两种疾病相似的临床和病理组织学特征提示Wnt和mTOR信号之间可能存在功能联系。具体目标是： 目的1：确定Wnt信号在体内和体外是否促进骨组织中mTOR活性。 目的2：阐明Wnt信号调节mTOR活性的潜在机制。 目的3.确定WNT对骨的合成代谢效应是否需要mTOR。 这些特定目标的成功完成将1)为Wnt信号对骨骼的合成代谢作用的分子机制提供关键的见解，2)为两种硬化性骨发育不良，即HBM和TSC骨病变所共有的相似的临床和病理组织学特征提供合理的解释，以及3)涉及mTOR的特异性抑制剂雷帕霉素及其衍生物，用于治疗由Wnt信号过度激活引起的硬化性骨病。

DESCRIPTION (provided by applicant): Osteoporosis is a leading public health problem that is characterized by reduced bone mass and bone mineral density. Wnt signaling promotes postnatal bone mass accrual. Our long-term goal is to elucidate the molecular mechanisms underlying the anabolic effects of Wnt signaling pathway on bone. We hypothesize that, in osteoblasts, 1) Wnt signaling regulates mTOR (mammalian homolog of target of rapamycin) activity, an essential serine/threonine kinase that plays a central role in regulating protein synthesis and cell growth; and 2) mTOR plays a critical role in mediating Wnt's anabolic effects on bone. These hypotheses are based on: 1) our biochemical analyses have demonstrated that the Wnt signaling pathway regulates mTOR activity in non-osteoblasts both in vivo and in vitro; and 2) both autosomal dominant high bone mass disease (HBM) and tuberous sclerosing bone dysplasia (TSC) are featured by osteoblastic and osteosclerotic changes in skeletal and craniofacial bones, thus both having being classified to sclerosing bone dysplasia; in these two diseases, hyperactivity of Wnt and mTOR signaling are implicated, respectively. The similar clinical and pathohistological features of these two diseases suggest a possible functional linkage between Wnt and mTOR signaling. The Specific Aims are: Aim 1: Determine whether Wnt signaling promotes mTOR activity in bone, both in vivo and in vitro. Aim 2: Elucidate the underlying mechanisms by which Wnt signaling regulates mTOR activity. Aim 3. Determine whether mTOR is required for Wnt anabolic effects on bone. Successful completion of these specific aims will 1) shed critical insight into the molecular mechanism of Wnt signaling' anabolic effects on bone, 2) provide a logical explanation for the similar clinical and pathohistological features shared by two subtypes of sclerosing bone dysplasias, i.e. HBM and TSC bone lesions, and 3) implicates rapamycin, a specific mTOR inhibitor, and the derivatives in treating sclerosing bone diseases caused by hyperactive Wnt signaling.