Does increasing bone mass also increase bone strength in mouse models of OI?

增加骨量是否也会增加成骨不全小鼠模型的骨强度?

基本信息

  • 批准号:
    8334034
  • 负责人:
  • 金额:
    $ 15.12万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-09-16 至 2014-08-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): We and other investigators have demonstrated the importance of LRP5 and LRP6 signaling for affecting bone mass and bone strength in humans and in mice. We now intend to test the hypothesis that enhancing LRP5/6 signaling, to increase bone mass and reduce bone degradation, will be beneficial in mouse models of the human skeletal disorder Osteogenesis Imperfecta (OI). This is high risk, because we may find that increasing bone mass, without fixing the underlying genetic defect, does not increase bone strength or reduce fracture risk in mouse models of OI. This result would be important, since it should temper enthusiasm for testing anabolic therapies that do not address the underlying genetic cause of OI in human patients. HOWEVER, if we find that increasing bone mass also increases bone strength and reduces fracture rates in mouse models of OI, then this would be high impact because it would suggest that anabolic therapies would benefit humans with OI. Nearly 28,000 US citizens have OI. Human OI is clinically and genetically heterogeneous, with most patients (>85%) having mutations in the genes encoding type 1 collagen. Therefore, we will study 3 mouse models of OI, all with type 1 collagen mutations, but with phenotypes that range from mild to severe. This will enable us to determine whether the type of collagen mutation (haploinsufficiency, missense, in-frame deletion) and the severity of the clinical phenotype affect the skeleton's response to enhanced LRP5/6 signaling. We will enhance LRP5/6 signaling in mice by two approaches. In the first approach we will use mice we have already created that have an Lrp5 high bone mass knockin allele (Lrp5HBM). These mice have substantially increased bone mass and bone strength compared to wild-type mice. In the second approach, we will use a mouse monoclonal antibody against SOST, an endogenous LRP5/6 inhibitor. This anti-SOST antibody increased bone mass in mice and in rats, and a humanized version increased bone mass in a primate model and is currently being tested in an FDA approved phase II clinical trial for osteopenia. Aim 1 involves crossing mice with the Lrp5HBM allele to mice with OI alleles to determine whether the Lrp5HBM allele increases bone mass and bone strength, and reduces fracture rates. Aim 2 administers the murine anti-SOST monoclonal antibody to OI mice in order to determine whether increasing LRP5 and LRP6 signaling, by inhibiting SOST, increases bone mass and bone strength, and reduces fracture rates in the mouse models of OI. We hope to show that modulating LRP5/6 signaling increases bone mass and bone strength in mouse models of OI. This result would be an important proof of principle to support more detailed studies regarding the optimal timing of therapy in animal models and to look for unexpected deleterious outcomes. Ultimately this knowledge will determine whether modulators of the LRP5/6 signaling pathway, or other therapies that are anabolic in wild-type bone, can be used to improve bone properties in human patients who have OI.
描述(由申请人提供):我们和其他研究人员已经证明了LRP 5和LRP 6信号传导对人类和小鼠骨量和骨强度的重要性。我们现在打算测试这一假设,即增强LRP 5/6信号传导,以增加骨量和减少骨降解,将有利于人类骨骼疾病成骨不全(OI)的小鼠模型。这是高风险的,因为我们可能会发现,在不修复潜在遗传缺陷的情况下,增加骨量不会增加骨强度或降低骨质疏松小鼠模型的骨折风险。这一结果将是重要的,因为它应该缓和测试合成代谢疗法的热情,这些疗法不能解决人类患者OI的潜在遗传原因。然而,如果我们发现增加骨量也会增加骨强度并降低OI小鼠模型的骨折率,那么这将是一个很大的影响,因为它表明合成代谢疗法将使OI患者受益。近28,000名美国公民患有OI。 人类OI在临床和遗传上是异质性的,大多数患者(>85%)在编码1型胶原蛋白的基因中具有突变。因此,我们将研究3种OI小鼠模型,所有模型均具有1型胶原突变,但表型范围从轻度到重度。这将使我们能够确定胶原蛋白突变的类型(单倍不足,错义,框内缺失)和临床表型的严重程度是否影响骨骼对增强的LRP 5/6信号传导的反应。我们将通过两种方法增强小鼠中的LRP 5/6信号传导。在第一种方法中,我们将使用我们已经创建的具有Lrp 5高骨量敲入等位基因(Lrp 5 HBM)的小鼠。与野生型小鼠相比,这些小鼠具有显著增加的骨量和骨强度。在第二种方法中,我们将使用针对内源性LRP 5/6抑制剂SOST的小鼠单克隆抗体。这种抗SOST抗体增加了小鼠和大鼠的骨量,人源化版本增加了灵长类动物模型的骨量,目前正在FDA批准的骨质减少II期临床试验中进行测试。目的1涉及将具有Lrp 5 HBM等位基因的小鼠与具有OI等位基因的小鼠杂交,以确定Lrp 5 HBM等位基因是否增加骨量和骨强度,并降低骨折率。目的2将鼠抗-SOST单克隆抗体给予OI小鼠,以确定通过抑制SOST增加LRP 5和LRP 6信号传导是否增加了OI小鼠模型中的骨量和骨强度,并降低了骨折率。我们希望表明,调节LRP 5/6信号增加骨质疏松症小鼠模型的骨量和骨强度。这一结果将是一个重要的原则证明,以支持更详细的研究,在动物模型中的最佳治疗时机,并寻找意想不到的有害结果。最终,这些知识将决定LRP 5/6信号通路的调节剂或其他在野生型骨中合成代谢的疗法是否可用于改善患有OI的人类患者的骨特性。

项目成果

期刊论文数量(0)
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Matthew L Warman其他文献

Directed differentiation of human pluripotent stem cells into articular cartilage reveals effects caused by absence of emWISP3/em, the gene responsible for progressive pseudorheumatoid arthropathy of childhood
人多能干细胞向关节软骨的定向分化揭示了由于缺乏 emWISP3/em(负责儿童进行性假类风湿性关节炎的基因)而引起的影响
  • DOI:
    10.1136/ard-2023-224304
  • 发表时间:
    2023-12-01
  • 期刊:
  • 影响因子:
    20.600
  • 作者:
    Chaochang Li;Mireia Alemany-Ribes;Rosanne M Raftery;Uzochi Nwoko;Matthew L Warman;April M Craft
  • 通讯作者:
    April M Craft

Matthew L Warman的其他文献

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{{ truncateString('Matthew L Warman', 18)}}的其他基金

Conditional mouse models with dominant negative Osteogenesis Imperfecta
显性负性成骨不全的条件小鼠模型
  • 批准号:
    10646852
  • 财政年份:
    2023
  • 资助金额:
    $ 15.12万
  • 项目类别:
Skeletal and non-skeletal roles for osteocalcin
骨钙素的骨骼和非骨骼作用
  • 批准号:
    10417887
  • 财政年份:
    2022
  • 资助金额:
    $ 15.12万
  • 项目类别:
Skeletal and non-skeletal roles for osteocalcin
骨钙素的骨骼和非骨骼作用
  • 批准号:
    10595042
  • 财政年份:
    2022
  • 资助金额:
    $ 15.12万
  • 项目类别:
Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta
成骨不全小鼠模型的神经行为表型
  • 批准号:
    10416072
  • 财政年份:
    2021
  • 资助金额:
    $ 15.12万
  • 项目类别:
Neurobehavioral phenotypes of mouse models of Osteogenesis Imperfecta
成骨不全小鼠模型的神经行为表型
  • 批准号:
    10303525
  • 财政年份:
    2021
  • 资助金额:
    $ 15.12万
  • 项目类别:
The Efficacy of combination therapy in Osteogenesis Imperfecta
联合治疗成骨不全症的疗效
  • 批准号:
    8900679
  • 财政年份:
    2015
  • 资助金额:
    $ 15.12万
  • 项目类别:
Mechanistic and Therapeutic Insights into Skeletal Biology Learned from the Study
从研究中获得的骨骼生物学机制和治疗见解
  • 批准号:
    8720467
  • 财政年份:
    2014
  • 资助金额:
    $ 15.12万
  • 项目类别:
Non-heritable genetic diseases of the skeletal system: Pathogenesis and Treatment
骨骼系统非遗传性遗传疾病:发病机制和治疗
  • 批准号:
    9052710
  • 财政年份:
    2014
  • 资助金额:
    $ 15.12万
  • 项目类别:
Non-heritable genetic diseases of the skeletal system: Pathogenesis and Treatment
骨骼系统非遗传性遗传疾病:发病机制和治疗
  • 批准号:
    8830919
  • 财政年份:
    2014
  • 资助金额:
    $ 15.12万
  • 项目类别:
Non-heritable genetic diseases of the skeletal system: Pathogenesis and Treatment
骨骼系统非遗传性遗传疾病:发病机制和治疗
  • 批准号:
    9245631
  • 财政年份:
    2014
  • 资助金额:
    $ 15.12万
  • 项目类别:

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