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

描述（由申请人提供）：骨是一种动态组织，需要生理或机械刺激来维持健康和功能。然而，诸如微重力和固定等条件会阻止骨负荷，从而导致骨吸收和骨形成的失调；因此，容易使骨头骨折。在口腔内，牙齿用来对颌骨施加负荷，维持骨矿物质密度和完整性。在牙齿完全脱落的无牙患者中，下颌骨经历高水平的骨吸收，导致骨含量低，增加骨折的风险。矿物质含量低使牙齿治疗和骨折愈合变得复杂。因此，了解机械负荷和缺乏对骨重塑的影响是非常必要的。骨细胞被认为是骨的机械传感器，负载刺激骨细胞成骨活性，卸载诱导骨细胞凋亡。一个值得注意的骨细胞蛋白是硬化蛋白，它通过抑制Wnt通路抑制成骨细胞活性。基于我们的初步数据，我们假设在机械敏感性骨重塑过程中，Sclerostin受到TGF -¿的调节。为了验证这一假设，我们将定义TGF¿、Smad2/3、SOST与长骨和颌骨机械刺激的关系。我们将在后肢加载模型（功能获得方法）中评估TGF -信号，并在颌骨废弃模型（功能丧失方法）中评估TGF -对卸载的响应。我们还将使用体外系统来确定TGF¿调节SOST活性的机制。我们提出的研究将揭示TGF¿调节硬化蛋白对机械敏感性骨重塑的调节机制。更清楚地了解机械敏感性骨形成的途径将为药物开发提供靶点，以治疗因牙齿缺失而导致的骨质流失。

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.