The recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1^G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1^G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

最近在 XV 型成骨不全症 (OI-XV) 个体中发现的纯合 WNT1 突变表明 WNT1 是促进成骨成骨细胞分化和功能的关键配体。尽管随后的研究支持了这种影响，但 OI-XV 的小鼠模型仍有待建立。因此，我们将先前确定的致病突变（G177C）引入小鼠Wnt1基因。纯合Wnt1 ^G177C/G177C小鼠可以存活并且没有表现出大脑发育缺陷，但大多数 24 周龄Wnt1 ^G177C/G177C老鼠有骨骼骨折。这种增加的骨脆性不能完全由骨量减少和骨基质质量受损来解释。重要的是， G177C的纯合存在突变不干扰甲状旁腺激素注射或激活 LRP5 突变的骨合成代谢影响，后者模仿硬化素中和的作用。最后，转录组学分析表明，对成骨细胞短期施用 WNT1 不仅诱导了经典 WNT 信号靶标的表达，而且还诱导了编码细胞外基质修饰物的基因的表达。总之，我们的数据表明调节骨基质质量是 WNT1 的主要功能。他们进一步建议具有 WNT1 突变的个体应该从现有的骨合成代谢疗法中获益。