Intersection of TGF-b and SOST in the Regulation of Load-induced Bone Formation

描述(申请人提供)：骨骼是一种动态组织，需要生理或机械刺激才能保持健康和功能。然而，微重力和固定等条件阻止了骨的加载，导致骨吸收和骨形成的失调，从而使骨容易骨折。在口腔中，牙齿被用来向颌骨施加载荷，以保持骨矿密度和完整性。在牙齿完全缺失的无牙颌患者中，下颌骨经历了高水平的骨吸收，导致骨含量低，增加了骨折的风险。矿物质含量低，使牙科治疗和骨折的愈合变得复杂。因此，了解机械负荷和机械负荷的缺乏对骨重建的影响是非常必要的。骨细胞被认为是骨中的机械传感器，具有负荷刺激骨细胞成骨活性和卸载诱导骨细胞凋亡的作用。一种值得注意的骨细胞蛋白是硬化素，它通过抑制Wnt途径来抑制成骨细胞的活动。根据我们的初步数据，我们假设在机械敏感的骨重建过程中，硬化素受到转化生长因子的调节。为了验证这一假设，我们将定义长骨和颌骨中转化生长因子β、Smad2/3、SOST和机械刺激的关系。我们将评估后肢负荷模型中的转化生长因子信号，功能获得法，以及颌骨废弃模型中的转化生长因子对卸载的反应，功能丧失法。我们还将使用体外系统来确定转化生长因子调节SOST活性的机制。我们建议的研究将揭示转化生长因子用于调节硬化素对机械敏感性骨重建的调节机制。更清楚地了解参与机械敏感骨形成的途径将为药物开发提供靶点，用于治疗因停用而导致的骨丢失，如无牙本质。

DESCRIPTION (provided by applicant): Bone is a dynamic tissue that requires physiological or mechanical stimulation to maintain health and function. However, conditions such as microgravity and immobilization prevent bone from being loaded causing a misregulation of bone resorption and bone formation; thus, predisposes the bone to fractures. In the oral cavity, teeth are used to apply load to the jawbone maintaining the bone mineral density and integrity. In edentulous patients, who have complete loss of teeth, the mandibular bone undergoes high level of bone resorption leading to low bone content and increase risk for fractures. The low mineral content complicates dental treatments and healing of the fractured bone. Therefore, it is imperative to understand how mechanical load and lack there of affect bone remodeling. Osteocytes have been implicated to be the mechanosensor in bone with load stimulating osteocyte bone formation activity and unload inducing osteocytes apoptotsis. A notable osteocyte protein is Sclerostin, which represses osteoblast activity by inhibiting the Wnt pathway. Based on our preliminary data, we hypothesize that Sclerostin is regulated by TGF¿ during mechanosensitive bone remodeling. To test this hypothesis, we will define the relationship of TGF¿, Smad2/3, SOST, and mechanical stimulation in the long bone and the jaw. We will evaluate TGF¿ signaling in a hindlimb loading model, a gain-of-function approach, and TGF¿ response to unloading with a disuse model in the jaw, a loss-of-function approach. We will also use an in vitro system to define the mechanisms that TGF¿ regulate SOST activity. Our proposed research will reveal the regulatory mechanisms used by TGF¿ to modulate Sclerostin for mechanosensitive bone remodeling. Clearer understanding of pathways involved in mechanosensitive bone formation would provide targets for drug development for treating bone loss due to disuse like in edentulism.