Cellular and molecular characterization of a mouse model for WNT1-related autosomal recessive osteogenesis imperfecta

Wnt信号通路是控制骨重建的最重要的调控机制之一。尽管目前尚不清楚已知的19个配体中的哪一个是主要的成骨分子，但越来越多的证据表明，WNT1是骨形成过程中的关键角色之一。事实上，尽管在早发性骨质疏松症患者中发现了WNT1杂合子突变，但WNT1纯合子突变会导致严重的儿童期骨质疏松症，被归类为XV型成骨不全。IOBM产生的数据支持WNT1在骨代谢中的相关性，因为在成骨细胞中可诱导表达WNT1的小鼠模型显示，由于成骨细胞活动增加，骨量显著增加。类似地，我们在成骨细胞特异性Wnt1缺失的小鼠模型中观察到骨量减少和骨折风险增加，而依赖Wnt1的早发性骨质疏松症小鼠模型显示骨小梁和皮质骨质量显著减少。本应用旨在表征携带Wnt1特定突变(G177C)的小鼠模型，该突变以前在成骨不全X型患者中被发现。初步结果表明，这些动物不仅表现出骨小梁和皮质骨量减少，而且骨折风险显著增加。在这项建议中，将涉及：(I)表型是否主要由骨基质质量受损或骨重塑改变引起，(Ii)哪些下游通路介导WNT1的骨合成代谢作用，以及(Iii)特雷帕雷或抗吸收治疗是否会对表型产生积极影响。预期的结果不仅可以优化WNT1突变患者的治疗，还可以为开发治疗不同骨骼疾病的新治疗方案奠定基础。

The Wnt signaling pathway is emerging as one of the most important regulatory mechanisms controlling bone remodeling. Although it is still unclear, which of the 19 known ligands acts as the primary osteoanablic molecule, there is increasing evidence that Wnt1 is one of the key players in the context of bone formation. In fact, whereas heterozygous WNT1 mutations were identified in patients with early-onset osteoporosis, homozygous WNT1 mutations cause severe childhood osteoporosis, classified as osteogenesis imperfecta type XV. Data generated by the IOBM support the relevance of Wnt1 in bone metabolism, since a mouse model with inducible Wnt1 expression in osteoblasts displayed a marked increase in bone mass due to increased osteoblast activity. Similarly, we observed reduced bone mass and increased fracture risk in a mouse model with osteoblast-specific Wnt1 deletion, whereas a mouse model of Wnt1-dependent early-onset osteoporosis displayed a significant reduction of trabecular and cortical bone mass.The present application aims at characterizing a mouse model carrying a specific mutation (G177C) of Wnt1, which was previously identified in a patient with osteogenesis imperfecta type XV. Initial results indicate that these animals do not only display reduced trabecular and cortical bone mass, but also a markedly increased fracture risk. In this proposal it will be addressed, (i) if the phenotype is primarily caused by an impaired quality of the bone matrix or by altered bone remodeling, (ii) which downstream pathways are mediating the osteoanabolic effect of Wnt1, and (iii) if teriparatide or anti-resorptive treatment will positively influence the phenotype. The expected results could not only optimize the treatment of patients with WNT1 mutations, but also be a basis for development of novel therapeutic options to treat different skeletal disorders.