在严重成骨不全小鼠模型中,增强Wnt信号可降低骨折发生率。

IF 3.6
Bone Pub Date : 2025-09-11 DOI:10.1016/j.bone.2025.117641
Giulia Montagna, Stephanie Lee, Austin Baacke, Matthew L Warman, Christina M Jacobsen
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引用次数: 0

摘要

骨折增加是骨骼疾病成骨不全症(OI)的一个标志性特征。一种抗硬化蛋白(一种内源性Wnt信号抑制剂)的中和抗体已被fda批准用于治疗骨质疏松症,目前正在进行治疗OI的临床试验。这种抗硬化抗体增加了几个临床前成骨不全模型的骨量和骨骼强度。由于体内骨折发生率是人类成骨不全症临床试验的主要指标,因此我们在严重常染色体显性成骨不全症的临床前小鼠模型(Col1a1Aga2/+小鼠)中检测了增强Wnt信号的作用。我们利用Lrp5A214V等位基因从基因上增强了Wnt信号,这使得Wnt共受体LRP5对硬化蛋白抑制具有抗性。通过将Col1a1Aga2/+基因与Lrp5A214V/+基因杂交,我们获得了仅具有OI的幼崽和具有OI +增强Wnt信号的幼崽。我们对这些动物在5、9和13 周龄时的骨折进行了x线检查,并使用Holeboard试验测量了它们的活动能力。我们发现,增强的Wnt信号显著降低了该OI模型中每个年龄段的骨折次数30 %,但对活动能力没有影响。这些数据表明,在严重成骨不全症的临床前模型中,增强的Wnt信号可降低骨折发生率,并表明可以通过向成骨不全症患者注射抗硬化蛋白抗体来降低骨折发生率。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhancing Wnt signaling lowers fracture incidence in a severe mouse model of Osteogenesis Imperfecta.

Increased fracture is a hallmark feature of the skeletal disorder Osteogenesis Imperfecta (OI). A neutralizing antibody against sclerostin, an endogenous Wnt signaling inhibitor, has been FDA-approved for osteoporosis and is now in clinical trials for OI. This anti-sclerostin antibody increased bone mass and skeletal strength in several preclinical models of OI. Because in vivo fracture incidence is the primary outcome measure in human OI clinical trials, we examined the effect of enhancing Wnt signaling in a preclinical mouse model of severe, autosomal dominant OI (the Col1a1Aga2/+ mouse). We genetically enhanced Wnt signaling using the Lrp5A214V allele, which makes the Wnt co-receptor LRP5 resistant to sclerostin inhibition. By crossing Col1a1Aga2/+ sires with Lrp5A214V/+ dams, we generated pups with OI alone and pups with OI plus enhanced Wnt signaling. We radiographically examined these animals for fractures at 5, 9, and 13 weeks of age and also measured their mobility using a Holeboard assay. We found that enhanced Wnt signaling significantly reduced fracture numbers in this OI model by 30 % at each age but did not significantly affect mobility. These data indicate that an enhanced Wnt signaling decreases fracture incidence in a preclinical model of severe OI and suggest that lower fracture rates could be achieved by administering anti-sclerostin antibodies to OI patients.

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