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）：使用抗骨吸收剂治疗骨质疏松症有局限性，部分原因是它们无法维持骨形成和骨转换1。据信，转换抑制是导致颌骨骨坏死和非典型股骨骨折等副作用的重要原因。在这种背景下，寻找新奇