L ow-density lipoprotein receptor-related protein 5 (LRP5) was identified as a major contributor to bone health when loss-offunction mutations in LRP5 were discovered to be associated with the autosomal recessive osteoporosis-pseudoglioma syndrome, a syndrome characterized by low bone mass (1,2) and when heterozygous missense mutations in LRP5 were observed in individuals with a dominantly inherited high-bone-mass (HBM) phenotype. (3)(4)(5) Decreased or increased bone formation was shown respectively to be the predominant underlying alteration in bone turnover in these phenotypes. These observations led to studies to elucidate the underlying mechanism of LRP5 effects on bone.
Wnt proteins are a family of secreted glycoproteins that are active in many cells and that control multiple developmental processes, including mesoderm induction, cell fate determination, limb patterning, and organogenesis; they also have been implicated in oncogenesis. (6) Wnts may induce signals through several intracellular cascades. In the canonical pathway, Wnt binds to a receptor complex that includes both a member of the frizzled (Fzd) family of seven-transmembrane receptors and of the single-pass members of the LRP family of membrane receptors, for example, LRP5 and LRP6 (Fig. 1). Binding of Wnt ligands to the Fzd/LRP5 or LRP6 complex results in phosphorylation of the intracellular cytoplasmic tail of Lrp5 or Lrp6. This disrupts an intracellular protein ''destruction'' complex that otherwise facilitates the phosphorylation of b-catenin by glycogen synthase kinase 3b (GSK3b) and targets b-catenin for ubiquitin-dependent proteolytic degradation. When b-catenin degradation is reduced, increased levels of nuclear b-catenin result that interact with transcription factors of the Tcf/Lef family to activate specific gene expression programs in target cells. Several in situ, ex vivo, and in vitro studies have reported that LRP5 can function as a coreceptor in the canonical signaling cascade of Wnt in bone, (1,7,8) ultimately resulting in increased bone formation. In vitro studies also have shown that secreted antagonists for Wnt signaling, such as Dickkopf1 (DKK1), or sclerostin may bind to LRP5 (or LRP6) (7,8) and in so doing antagonize Wnt signaling through LRP5 (or LRP6). LRP5