Mice carrying a ubiquitous R235W mutation of Wnt1 display a bone ‐specific phenotype

ABSTRACTSince a key function of Wnt1 in brain development was established early on through the generation of non ‐viableWnt1‐deficient mice, it was initially surprising thatWNT1 mutations were found to cause either early ‐onset osteoporosis (EOOP) or osteogenesis imperfecta type XV (OI‐XV). The deduced function of Wnt1 as an osteoanabolic factor has been confirmed in various mouse models with bone‐specific inactivation or over‐expression, but mice carrying disease‐causingWnt1 mutations have not yet been described. Triggered by the clinical analysis of EOOP patients carrying a heterozygousWNT1 mutation (p.R235W), we introduced this mutation into the murineWnt1 gene to address the question, whether this would cause a skeletal phenotype. We observed thatWnt1+/R235W andWnt1R235W/R235W mice were born at the expected Mendelian ratio and that they did not display postnatal lethality or obvious non ‐skeletal phenotypes. At 12 weeks of age, the homozygous presence of theWnt1 mutation was associated with reduced trabecular and cortical bone mass, explained by a lower bone formation rate as compared to wildtype littermates. At 52  weeks of age, we also observed a moderate bone mass reduction in heterozygousWnt1+/R235W mice, thereby underscoring their value as a model of WNT1 ‐dependent EOOP. Importantly, when we treated wildtype andWnt1+/R235W mice by daily injection of parathyroid hormone (PTH), we detected the same osteoanabolic influence in both groups, together...
Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research