Lrp5 functions in bone to regulate bone mass

Abstract

The human skeleton is affected by mutations in Low-density lipoprotein Receptor-related Protein 5 (LRP5). To understand how LRP5 influences bone properties, we generated mice with inducible Lrp5 mutations that cause high bone mass and low bone mass phenotypes in humans. We conditionally-induced Lrp5 mutations in osteocytes and found that bone properties in these mice were comparable to bone properties in mice with inherited mutations. We also conditionally-induced an Lrp5 mutation in cells that contribute to the appendicular skeleton, and not to the axial skeleton, and we observed bone properties were altered in the limbs, and not in the spine. These data indicate that Lrp5 signaling functions locally and suggest increasing LRP5 signaling in mature bone cells as a strategy to treat human low bone mass disorders, such as osteoporosis.

Canonical Wnt signaling inhibits osteoclastogenesis independent of osteoprotegerin

“…debate regarding the mechanism of Lrp5 action (Yadav et al, 2008;Cui et al, 2011). What is obvious, however, is that ubiquitous inactivation of Lrp5 causes a bone-remodeling phenotype that is fundamentally different from the phenotypes observed in various mouse models with cell type-specific inactivation of -catenin.…”

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

“…(12,14,15) Controversial data have been published concerning the osteoblastic cell autonomous function of the Lrp5/b-catenin pathway in controlling bone metabolism. (18,19) Despite this controversy, there is in vivo evidence for a negative regulation of bone formation by Wnt antagonists such as DKK1, Krm2, or Sfrp1. (20)(21)(22)(23) These observations supported the existence of an in vivo cell autonomous effect of Wnts in osteoblasts.…”

Targeted deletion of Sost distal enhancer increases bone formation and bone mass

“…osteocytes S everal rare genetic disorders that interfere with Wnt signaling have provided strong evidence that the "canonical" Wnt signaling pathway is critical in bone (1). The Wnt coreceptor LRP5 has been described as a modulator of bone mass where loss-offunction mutations cause osteoporosis-pseudoglioma syndrome (OPPG) (2), an autosomal recessive disorder characterized by low bone mass and skeletal fragility; conversely, gain-of-function Lrp5 alleles cause high bone mass (HBM) (3). Similar hyperactive osteoblast activity due to elevated Wnt signaling was observed when Sost, a secreted Wnt inhibitor, was mutated in knockout (KO) mice or in sclerosteosis patients who suffer from generalized hyperostosis (4-6).…”