<i>Cbfa1</i>-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

TLDR

Lrp5 is a Wnt coreceptor expressed in osteoblasts and essential for optimal Wnt signaling in bone formation. The low‑bone‑mass phenotype emerges postnatally due to reduced osteoblast proliferation and function independent of Cbfa1. Lrp5‑deficient mice display low bone mass, persistent embryonic eye vascularization from failed macrophage‑induced endothelial apoptosis, and these phenotypes recapitulate human osteoporosis‑pseudoglioma syndrome, highlighting Wnt’s role in postnatal bone and vascular regression.

Abstract

The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.