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

TGF-b 和 SOST 在负荷诱导骨形成调节中的交叉作用

• 批准号: 8691408
• 负责人: Jacqueline Nguyen
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8691408
• 关键词: Ablation; Adult; Affect; Bone Density; Bone Diseases; Bone Resorption; Bone remodeling; Cells; Data; Dental; Diagnosis; Disease; Dominant Negative Receptor; Dominant-Negative Mutation; Down-Regulation; Edentulous Mouth; Exercise; Exhibits; Fracture; Fracture Healing; Gene Expression; Gene Expression Profiling; Genes; Goals; Health; Hindlimb; Human; Immobilization; Immunohistochemistry; In Vitro; Jaw; Life Expectancy; Luciferases; Maintenance; Mandible; Mastication; Masticatory muscles; Mechanical Stimulation; Mechanics; Mediating; Microgravity; Minerals; Modeling; Molecular; Mus; Mutation; National Health and Nutrition Examination Survey; Oral cavity; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Osteosclerosis; Paralysed; Pathway interactions; Patients; Physical Stimulation; Physiological; Proteins; Regimen; Regulation; Reporter; Reporting; Research; Risk; Signal Pathway; Signal Transduction; System; Testing; Tissues; Tooth Loss; Tooth structure; Transgenic Mice; Wild Type Mouse; X-Ray Computed Tomography; aging population; base; bone; bone loss; bone mass; bone metabolism; craniofacial complex; drug development; edentulism; gain of function; human old age (65+); in vivo; long bone; loss of function; overexpression; prevent; promoter; response; skeletal; small hairpin RNA; success; therapeutic development

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.

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来维持健康和功能。然而，诸如微重力和固定的条件阻止骨被加载，导致骨吸收和骨形成的失调;因此，使骨易于骨折。在口腔中，牙齿用于向颌骨施加载荷，以保持骨矿物质密度和完整性。在牙齿完全缺失的无牙患者中，下颌骨经历高水平的骨吸收，导致骨含量低并增加骨折的风险。低矿物质含量使牙科治疗和骨折愈合复杂化。因此，了解机械负荷和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力学传感器，负荷刺激骨细胞的骨形成活性，卸载诱导骨细胞的骨破坏。一种值得注意的骨细胞蛋白是硬化蛋白，其通过抑制Wnt途径来抑制成骨细胞活性。基于我们的初步数据，我们假设在机械敏感性骨重建过程中，硬化蛋白受TGF？调节。为了验证这一假设，我们将确定TGF β，Smad 2/3，SOST和机械刺激在长骨和颌骨中的关系。我们将评估TGF？后肢负荷模型中的信号传导，一种功能获得方法，以及颌骨中的废用模型中的TGF β对卸载的反应，一种功能丧失方法。我们还将使用体外系统来定义TGF β调节SOST活性的机制。我们提出的研究将揭示TGF β用于调节硬化蛋白的机械敏感性骨重建的调节机制。更清楚地了解机械敏感性骨形成的途径，将为治疗因废用（如缺牙）引起的骨丢失的药物开发提供靶点。