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

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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.