Impact of Wnt1 mutation on skeletal remodeling, bone matrix quality, fracture healing and response to mechanical stimulation

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Understanding the molecular regulation of bone-forming osteoblasts is of tremendous clinical importance, as it might pave the way to develop novel osteoanabolic treatment options. The key impact of the Wnt signaling pathway for controlling osteoblast activity has been demonstrated by several means, including genetic data, obtained not only in mice, but also in humans with inherited bone disorders. We, and others have recently identified heterozygous WNT1 mutations in individuals with early-onset osteoporosis, whereas homozygous WNT1 mutations were found to cause a more severe childhood bone disorder, classified as osteogenesis imperfecta type XV (OI-XV). We could also show that inactivation of Wnt1 in osteoblast lineage cells causes low bone mass with accompanying fractures, whereas inducible Wnt1 expression in osteoblasts causes a rapid osteoanabolic response in a transgenic mouse model.For the present project we will focus on another mouse model, where we have introduced the G177C mutation, previously identified in a patient with OI-XV, into the murine Wnt1 gene. The resulting Wnt1G177C/G177C mice, unlike Wnt1-/- mice, did not display a detectable brain abnormality, but their bone mass was significantly reduced already at 4 weeks of age. At the age of 6 months we observed a high incidence of spontaneous fractures in Wnt1G177C/G177C mice, and histological analysis of the fracture callus indicated an unusual accumulation of adipocytes. It is also noteworthy that the high fracture incidence of the Wnt1G177C/G177C mice occurred despite only moderate osteopenia, thereby suggesting that Wnt1 mutation profoundly affects bone matrix composition and quality. The collaboration between our two groups aims at i) understanding the molecular function of Wnt1 in osteoblasts, ii) defining the responsible receptor (complex) mediating the osteoanabolic influence of Wnt1, iii) assessing the impact of Wnt1 mutation on fracture healing in an established osteotomy model, and iv) analyzing the putative role of Wnt1 as a mediator of the osteoanabolic response towards mechanical loading. Our combined efforts will generate additional molecular knowledge on the critical role of Wnt1 in the skeleton. This might pave the way for the development of novel drugs specifically increasing osteoblast activity and bone quality in the context of physiological bone remodeling or bone regeneration.