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 osteo...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 aninfluence 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.展开更多
基金This project has received funding from the Deutsche Forschungsgemeinschaft(SCHI 504/15-1 and YO 299/1-1),the European Community's Seventh Framework Programme under grant agreement no.602300(SYBIL),and the German Federal Ministry of Education and Research(BMBF)within the project"Detection and Individualized Management of Early Onset Osteoporosis(DIMEOS)"Parts of this work were supported by the Deutsche Forschungsgemeinschaft through FOR 2722 to O.S.(SE2373/1-1)W.Z.received funding through the China Scholarship Council.
文摘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 aninfluence 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.
