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

描述(由申请人提供)：我们和其他研究人员已经证明了LRP5和LRP6信号对影响人类和小鼠的骨量和骨强度的重要性。我们现在打算在人类骨骼疾病成骨不全(OI)的小鼠模型中检验这一假设，即增强LRP5/6信号转导，增加骨量和减少骨降解将是有益的。这是高风险的，因为我们可能会发现，在OI的小鼠模型中，增加骨量而不修复潜在的遗传缺陷，并不能增加骨骼强度或降低骨折风险。这一结果将是重要的，因为它应该缓和人们对测试合成代谢疗法的热情，这些疗法没有解决人类患者OI的潜在遗传原因。然而，如果我们在OI的小鼠模型中发现增加骨量也可以增加骨骼强度和降低骨折发生率，那么这将是非常有影响的，因为这将表明合成代谢疗法将使患有OI的人类受益。近2.8万名美国公民患有OI。人类OI在临床和遗传上是不同的，大多数患者(&gt；85%)都有编码1型胶原的基因突变。因此，我们将研究3种OI小鼠模型，它们都带有1型胶原突变，但表型从轻度到重度不等。这将使我们能够确定胶原突变的类型(单倍体不足、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LRP5/6信号的反应。我们将通过两种途径增强小鼠的LRP5/6信号转导。在第一种方法中，我们将使用我们已经创造的具有LRP5高骨量敲击等位基因(Lrp5HBM)的小鼠。与野生型小鼠相比，这些小鼠的骨量和骨强度都有很大提高。在第二种方法中，我们将使用鼠抗内源性LRP5/6抑制剂Sost的单抗。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批准的骨量减少症的II期临床试验中进行测试。目的1将携带Lrp5HBM等位基因的小鼠与携带OI等位基因的小鼠杂交，以确定Lrp5HBM等位基因是否增加骨量和骨强度，并降低骨折发生率。目的应用鼠抗SOST单抗对OI小鼠进行干预，以确定通过抑制SOST而增加LRP5和LRP6信号通路是否能增加OI小鼠的骨量和骨强度，降低OI小鼠的骨折发生率。我们希望通过调节LRP5/6信号通路增加OI小鼠的骨量和骨强度。这一结果将是一个重要的原则证据，支持关于动物模型最佳治疗时机的更详细研究，并寻找意想不到的有害结果。最终，这一知识将决定LRP5/6信号通路的调节器，或其他在野生型骨骼中进行合成代谢的疗法，是否可以用于改善OI患者的骨属性。

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.