Mice Carrying a Ubiquitous R235W Mutation of Wnt1 Display a Bone-Specific Phenotype

作者：Timur Yorgan, Tim Rolvien, Julian Stürznickel, Nele Vollersen, Fabiola Lange, Wenbo Zhao, Anke Baranowsky, Lana Rosenthal, Irm Hermans-Borgmeyer, Ahmed Sharaf, Meliha Karsak, Jean-Pierre David, Ralf Oheim, Michael Amling, Thorsten Schinke · 发表于：Journal of Bone and Mineral Research · 年份：2020 · DOI：10.1002/jbmr.4043 · 被引用次数：13 · 研究领域：Wnt/β-catenin signaling in development and cancer、Connective tissue disorders research、Fibroblast Growth Factor Research

ABSTRACT Since a key function of Wnt1 in brain development was established early on through the generation of non-viable Wnt1-deficient mice, it was initially surprising that WNT1 mutations were found to cause either early-onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OIXV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mousemodels with bone-specific inactivation or overexpression, but mice carrying disease-causing Wnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygous WNT1 mutation (p.R235W), we introduced thismutation into themurine Wnt1 gene to address the question of whether this would cause a skeletal phenotype. We observed that Wnt1+/R235W and Wnt1R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious nonskeletal phenotypes. At 12 weeks of age, the homozygous presence of the Wnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate compared with wild-type littermates. At 52 weeks of age, we also observed a moderate bone mass reduction in heterozygous Wnt1+/R235W mice, thereby underscoring their value as amodel of WNT1-dependent EOOP. Importantly, when we treated wild-type and Wnt1+/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together with an increased c...