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Significance Targeting WNT (Wingless-type)/β-catenin signaling has emerged as an attractive novel therapeutic approach to the treatment of bone diseases. We previously identified LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of action of the WNT signaling antagonist SOST/sclerostin in vitro. Here, we generated bone-specificLrp4 -deficient mouse lines and anti-LRP4 antibodies selectively disrupting the Lrp4 sclerostin facilitator function. Using these novel genetic and pharmacological tools, we demonstrate that disruption of Lrp4 function induces bone gain in vivo and results in highly elevated circulating sclerostin levels. Together, these findings provide important novel insights into the role of LRP4 as a key regulator of bone homeostasis and into the mode of action of sclerostin and provide a new strategy for promoting bone gain through targeting of the WNT pathway.

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels