LRP5: From bedside to bench to bone

Abstract

A role for low-density lipoprotein-related receptor 5 (LRP5) in human bone was first established by the identification of genetic alterations that led to dramatic changes in bone mass. Shortly thereafter, mutations that altered the function of the sclerostin (SOST) gene were also associated with altered human bone mass. Subsequent studies of LRP5 and sclerostin have provided important insights into the mechanisms by which these proteins regulate skeletal homeostasis. Sclerostin normally binds to LRP5 and the related LRP6 protein and prevents their activation by Wnts, the LRP5/LRP6 ligands. The interaction of sclerostin with LRP5 or LRP6 is facilitated by the LRP4 protein. Loss of LRP5 leads to defective osteoblast function and low bone mass, while loss of SOST or mutations in LRP5, which produce a protein that can no longer be bound by SOST, result in high bone mass. Insights gained from the use of genetically engineered mouse models are presented, as well as a brief summary of the status of antibodies in clinical trials that block the function of SOST as a mechanism to increase bone mass.

Keywords: Lrp5; Osteoblasts; Sclerostin; Wnt; β-Catenin.