Enhancing Wnt signaling lowers fracture incidence in a severe mouse model of Osteogenesis Imperfecta.

Increased fracture is a hallmark feature of the skeletal disorder Osteogenesis Imperfecta (OI). A neutralizing antibody against sclerostin, an endogenous Wnt signaling inhibitor, has been FDA-approved for osteoporosis and is now in clinical trials for OI. This anti-sclerostin antibody increased bone mass and skeletal strength in several preclinical models of OI. Because in vivo fracture incidence is the primary outcome measure in human OI clinical trials, we examined the effect of enhancing Wnt signaling in a preclinical mouse model of severe, autosomal dominant OI (the Col1a1Aga2/+ mouse). We genetically enhanced Wnt signaling using the Lrp5A214V allele, which makes the Wnt co-receptor LRP5 resistant to sclerostin inhibition. By crossing Col1a1Aga2/+ sires with Lrp5A214V/+ dams, we generated pups with OI alone and pups with OI plus enhanced Wnt signaling. We radiographically examined these animals for fractures at 5, 9, and 13 weeks of age and also measured their mobility using a Holeboard assay. We found that enhanced Wnt signaling significantly reduced fracture numbers in this OI model by 30 % at each age but did not significantly affect mobility. These data indicate that an enhanced Wnt signaling decreases fracture incidence in a preclinical model of severe OI and suggest that lower fracture rates could be achieved by administering anti-sclerostin antibodies to OI patients.