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

描述（由申请人提供）：我们和其他研究者已经证明了LRP5和LRP6信号在影响人类和小鼠骨量和骨强度方面的重要性。我们现在打算在人类骨骼疾病成骨不全症（Osteogenesis Imperfecta， OI）的小鼠模型中验证增强LRP5/6信号以增加骨量和减少骨退化的假设。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，增加骨量并不能增加骨强度或降低成骨不全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成骨不全的潜在遗传原因。然而，如果我们在成骨不全小鼠模型中发现增加骨量也能增加骨强度并降低骨折率，那么这将是高影响的，因为这将表明合成代谢疗法对成骨不全患者有益。近2.8万美国人患有成骨不全症。人类成骨不全在临床上和遗传上都是异质的，大多数患者（约85%）编码1型胶原蛋白的基因发生突变。因此，我们将研究3只成骨不全小鼠模型，它们都有1型胶原突变，但表型从轻微到严重不等。这将使我们能够确定胶原突变的类型（单倍不全、错义、框架内缺失）和临床表型的严重程度是否会影响骨骼对增强的LRP5/6信号的反应。我们将通过两种方法增强小鼠的LRP5/6信号。在第一种方法中，我们将使用我们已经创造的具有Lrp5高骨量敲入等位基因（Lrp5HBM）的小鼠。与野生型小鼠相比，这些小鼠的骨量和骨强度显著增加。在第二种方法中，我们将使用针对内源性LRP5/6抑制剂SOST的小鼠单克隆抗体。这种抗sost抗体在小鼠和大鼠中增加了骨量，人源化抗体在灵长类动物模型中增加了骨量，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是将携带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等位基因是否能增加骨量和骨强度，并降低骨折率。目的2通过小鼠抗SOST单克隆抗体对成骨不全小鼠进行治疗，以确定是否通过抑制SOST增加LRP5和LRP6信号，增加骨量和骨强度，降低成骨不全小鼠模型的骨折率。我们希望证明，在成骨不全小鼠模型中，调节LRP5/6信号可增加骨量和骨强度。这一结果将是一个重要的原则证明，支持在动物模型中进行更详细的研究，以确定最佳治疗时间，并寻找意想不到的有害结果。最终，这些知识将决定LRP5/6信号通路的调节剂，或其他在野生型骨中合成代谢的疗法，是否可以用于改善成骨不全患者的骨特性。

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. PUBLIC HEALTH RELEVANCE: There are nearly 28,000 US citizens who have the skeletal fragility syndrome Osteogenesis Imperfecta (OI). Most patients with OI have mutations in the genes that encode type 1 collagen. These mutations cause an abnormal bone matrix to be produced. The abnormal matrix, itself and the low bone mass that often accompanies it contribute to the patients' skeletal fragility. We want to determine whether increasing bone mass, without correcting the underlying genetic cause of OI, will be sufficient to increase bone strength and reduce the incidence of fractures in animal models of OI. This question is important since drugs are currently available and in clinical trials that do not correct the underlying genetic cause of OI, but which could be used to increase bone mass in humans with OI.