R-Spondin3 as a target for anabolic bone therapy

R-Spondin3 作为骨合成代谢治疗的靶点

基本信息

批准号：
9478548
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
项目类别：
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/9478548
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

项目摘要

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. 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. 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. 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. 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 β-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（由适用提供）：使用抗敏化药物治疗骨质疏松症具有部分限制，部分原因是它们无法维持骨形成和骨骼更新。人们认为，营业额抑制作用显着促进副作用，例如颌骨的骨坏死和股骨的非典型裂缝。在这种情况下，寻找小说增加骨骼质量和预防脆弱性碎片的手段已成为最重要的。 PTH是市场上唯一获得批准的合成代谢药物，可有效地增加骨形成，但也增加了骨骼分辨率，并且与动物研究中的骨肉瘤有关，从而限制了其长期使用。激活人类和小鼠中激活规范Wnt（C-WNT）信号传导突变的发现导致了强烈的合成代谢反应并增加了骨骼质量和升高，尽管目前正在激活Wnt信号传导的几种化合物中，例如在临床试验中，例如对硬化蛋白或DKK1的抗体，最近的临床发现表明了一些时间的临床形式，使我们的多个问题提出了多种问题，这些事实是造成的。骨骼中的信号传导仍然有限。我们在这里提议在小鼠中检验以下假设：抑制成人骨骼中的RSPO3可能是一种新型的骨质疏松症合成代谢方法。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缺失对体内骨体内平衡和体外骨细胞的影响2：探索体外和体内探索RSPO3的分子机制，RSPO3的分子机制会增加β-catenin稳定性的缺失以及Wnt信号。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水平的降低可以在啮齿动物中诱导强大的合成代谢反应，而意外地使这种固体调节剂家族成为治疗干预的潜在靶标。它们也直接翻译为AR，因为测试了成人骨骼中RSPO3表达的降低的影响，而OVX后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。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.

DOI：
10.1038/nm.3654
发表时间：
2014-11
期刊：
Nature medicine
影响因子：
82.9
作者：
通讯作者：

R-spondin 3 deletion induces Erk phosphorylation to enhance Wnt signaling and promote bone formation in the appendicular skeleton.

DOI：
10.7554/elife.84171
发表时间：
2022-11-02
期刊：
eLife
影响因子：
7.7
作者：
Nagano K;Yamana K;Saito H;Kiviranta R;Pedroni AC;Raval D;Niehrs C;Gori F;Baron R
通讯作者：
Baron R

Cortical-Bone Fragility--Insights from sFRP4 Deficiency in Pyle's Disease.

DOI：
10.1056/nejmoa1509342
发表时间：
2016-06-30
期刊：
The New England journal of medicine
影响因子：
0
作者：
Kiper POS;Saito H;Gori F;Unger S;Hesse E;Yamana K;Kiviranta R;Solban N;Liu J;Brommage R;Boduroglu K;Bonafé L;Campos-Xavier B;Dikoglu E;Eastell R;Gossiel F;Harshman K;Nishimura G;Girisha KM;Stevenson BJ;Takita H;Rivolta C;Superti-Furga A;Baron R
通讯作者：
Baron R

Sfrp4 and the Biology of Cortical Bone.