R-Spondin3 as a target for anabolic bone therapy

R-Spondin3 作为骨合成代谢治疗的靶点

• 批准号: 9250695
• 负责人: ROLAND E BARON
• 金额: $ 54.91万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9250695
• 关键词: Adult; Adverse effects; Affect; Animals; Antibodies; Binding; Bone Diseases; Bone Resorption; Bone necrosis; Cells; Clinical; Clinical Trials; Data; Development; Distal; Family; Femoral Fractures; G-Protein-Coupled Receptors; Health; Homeostasis; Human; In Vitro; Intuition; Investigation; Jaw; Knock-out; LGR5 gene; Lead; Leucine-Rich Repeat; Mammals; Medical; Modeling; Molecular; Molecular Mechanisms of Action; Mus; Mutation; Osteogenesis; Osteoporosis; Ovariectomy; Pathway interactions; Pharmaceutical Preparations; Proteins; Reporting; Rodent; Role; Skeleton; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; WNT Signaling Pathway; Xenopus; base; beta catenin; bone; bone cell; bone fragility; bone mass; bone strength; bone turnover; design; expectation; fragility fracture; in vivo; innovation; member; novel; osteosarcoma; postnatal; prevent; public health relevance; receptor; response; skeletal disorder; stem cell biology; syndecan-4; targeted treatment

DESCRIPTION (provided by applicant): The use of anti-resorptives to treat osteoporosis has limitations due in part to their inability to maintain bone formation and bone turnover 1. It is believed that turnover suppression is contributing significantly to side effects such as osteonecrosis of the jaw and atypical fractures of the femur. In this context, the search for novel means to increase bone mass and prevent fragility fractures has become of the utmost importance. PTH, the only approved anabolic drug on the market, increases efficiently bone formation but also increases bone resorption and has been associated with osteosarcoma in animal studies, limiting its long-term use 2. The discovery that activating canonical Wnt (C-Wnt) signaling mutations in humans and mice lead to strong anabolic responses and increase bone mass and strength raised significant hope to resolve this unmet medical need 3, 4. Although several compounds that activate Wnt signaling are currently in clinical trials, such as antibodies to sclerostin or Dkk1, recent clinical findings have shown a time-limited bone formation effect, raising multiple questions about their therapeutic use and illustrating the fact that our understanding of Wnt signaling in bone remains limited 4. We propose here to test in mice the hypothesis that inhibiting Rspo3 in the adult skeleton may be a novel anabolic approach to osteoporosis. The investigations in this proposal will elucidate the effects of deleting Rspo3 in postnatal bone homeostasis, the effects of antagonizing Rspo3 in the adult skeleton and in a model of osteoporosis and the mechanism(s) by which bone mass is increased. Our specific aims are: Specific Aim 1: Further analyze the effects of Rspo3 deletion on bone homeostasis in vivo and on bone cells in vitro and evaluate the effect of inducible OB-targeted deletion (Col1a1-CreERT2 /Rspo3f/f) of Rspo3 in the adult skeleton. Specific Aim 2: Explore in vitro and in vivo the molecular mechanisms by which deletion of Rspo3 increases b-catenin stabilization and thereby Wnt signaling. Specific Aim3: In parallel, establish a model of therapeutic intervention in osteoporosis by generating an inducible global Rspo3 knockout (R26ERCre/Rspo3f/f) to test the effects of Rspo3 reduction/deletion in the adult skeleton and after ovariectomy. The studies proposed in this application are innovative since our data reveal a novel and unexpected role of RSpondins in bone homeostasis, and significant because they demonstrate that reduction in the levels of RSpondins can induce a strong anabolic response in rodents, unexpectedly making this family of soluble Wnt regulators a potential target for therapeutic intervention. They also ar directly translational since testing the effects of reduction of RSPO3 expression in an adult skeleton and after OVX may have a significant impact on the treatment of osteoporosis, and other diseases of bone fragility.

描述（由申请人提供）：使用抗敏化药物治疗骨质疏松症具有局限性，部分原因是它们无法维持骨形成和骨转换1。据信，据信，抑制周转抑制作用对副作用产生了显着贡献，例如骨骼骨骼的骨质性和非典型骨折骨折。在这种情况下，寻找小说 增加骨骼质量和预防脆弱性骨折的手段已成为最重要的。 PTH是市场上唯一获得认可的合成代谢药物，可有效地增加骨骼的形成，但同时增加了骨吸收，并且与动物研究中的骨肉瘤有关，限制了其长期使用2。激活规范Wnt（C-C-WNT）信号突变的发现，在人类和小鼠中需要强烈的医疗反应和强大的强度，虽然可以升高这一巨大的强大，但它可以促进4点的强大升高。当前正在临床试验中，激活Wnt信号传导，例如对硬化蛋白或DKK1的抗体，最近的临床发现显示了时间限制的骨骼形成效应，这引发了多个问题，这些问题关于其治疗用途，并说明我们对骨骼中的Wnt信号的理解仍然有限4。我们在这里有限4.我们建议在小鼠中测试成人的成年人，以抑制成人的Skelet 3，抑制了Rysbore 3，这是抑制R的R.3骨质疏松症。该提案中的研究将阐明删除RSPO3在产后骨稳态中的影响，在成人骨骼中拮抗RSPO3的影响以及骨质疏松症的模型以及增加骨骼质量的机制。我们的具体目的是：具体目标1：进一步分析RSPO3缺失对体内骨稳态和体外骨细胞的影响，并评估成人骨骼中RSPO3的诱导型OB靶向缺失（COL1A1-CREERT2 /RSPO3F /F）的影响。特定目标2：在体外和体内探索分子机制，通过RSPO3的缺失增加了B-catenin稳定性并从而使WNT信号传导。特定的目标3：并行建立一种治疗干预模型 骨质疏松症通过产生可诱导的全局RSPO3敲除（R26ercre/rspo3f/f）来测试成人骨骼和卵巢切除术后RSPO3减少/缺失的影响。该应用中提出的研究具有创新性，因为我们的数据揭示了Rspondins在骨稳态中的新颖而出乎意料的作用，并且很重要，因为它们证明了Rspondins水平的降低会在啮齿动物中诱导强大的合成代谢反应，这意外使这一可溶性Wnt Wnt调节剂成为治疗干预的潜在靶标。它们也直接转化，因为测试了成人骨骼中RSPO3表达降低的影响，而OVX可能对骨质疏松症的治疗以及其他骨脆性疾病产生重大影响。