Expression of secreted frizzled related protein 1, a Wnt antagonist, in brain, kidney, and skeleton is dispensable for normal embryonic development

Secreted frizzled related protein-1 (sFRPI), an antagonist of Wnt signaling, regulates cell proliferation, differentiation and apoptosis and negatively regulates bone formation. The spatial and temporal pattern of endogenous sFRP I expression and loss-of-function were examined in the sFRP I -LacZ knock-in mouse (sFRPI(-/-)) during embryonic development and post-natal growth. P-gal activity representing sFRP I expression is robust in brain, skeleton, kidney, eye, spleen, abdomen, heart and somites in early embryos, but sFRP I gene inactivation in these tissues did not compromise normal embryonic and post-natal development. Kidney histology revealed increased numbers of glomeruli in KO mice, observed after 5 years of breeding. In the skeleton, we show sFRP I expression is found in relation to the mineralizing front of bone tissue during skeletal development from E 15.5 to birth. Trabecular bone volume and bone mineral density in the sFRPI(-/-) mouse compared to WT was slightly increased during post-natal growth. Calvarial osteoblasts from newborn sFRPI(-/-) mice exhibited a 20% increase in cell proliferation and differentiation at the early stages of osteoblast maturation. sFRP I expression was observed in osteoclasts, but this did not affect osteoclast number or activity. These findings have identified functions for sFRP I in kidney and bone that are not redundant with other sFRPs. In summary, the absence of major organ abnormalities, the enhanced bone formation and a normal life span with no detection of spontaneous tumors suggests that targeting sFRP I can be used as a therapeutic strategy for increasing bone mass in metabolic bone disorders or promoting fracture healing by modulating Writ signaling.