Lrp5 and Lrp6 Exert Overlapping Functions in Osteoblasts during Postnatal Bone Acquisition

Abstract

The canonical Wnt signaling pathway is critical for skeletal development and maintenance, but the precise roles of the individual Wnt co-receptors, Lrp5 and Lrp6, that enable Wnt signals to be transmitted in osteoblasts remain controversial. In these studies, we used Cre-loxP recombination, in which Cre-expression is driven by the human osteocalcin promoter, to determine the individual contributions of Lrp5 and Lrp6 in postnatal bone acquisition and osteoblast function. Mice selectively lacking either Lrp5 or Lrp6 in mature osteoblasts were born at the expected Mendelian frequency but demonstrated significant reductions in whole-body bone mineral density. Bone architecture measured by microCT revealed that Lrp6 mutant mice failed to accumulate normal amounts of trabecular bone. By contrast, Lrp5 mutants had normal trabecular bone volume at 8 weeks of age, but with age, these mice also exhibited trabecular bone loss. Both mutants also exhibited significant alterations in cortical bone structure. In vitro differentiation was impaired in both Lrp5 and Lrp6 null osteoblasts as indexed by alkaline phosphatase and Alizarin red staining, but the defect was more pronounced in Lrp6 mutant cells. Mice lacking both Wnt co-receptors developed severe osteopenia similar to that observed previously in mice lacking β-catenin in osteoblasts. Likewise, calvarial cells doubly deficient for Lrp5 and Lrp6 failed to form osteoblasts when cultured in osteogenic media, but instead attained a chondrocyte-like phenotype. These results indicate that expression of both Lrp5 and Lrp6 are required within mature osteoblasts for normal postnatal bone development.

Wnt-Lrp5 Signaling Regulates Fatty Acid Metabolism in the Osteoblast

“…1E) that may be attributed to a decrease in lean mass relative to control littermates (Fig. 1G) and the progressive loss of bone mass (6). Since there was no difference in the relative abundance of marrow adipocytes in control and ⌬Lrp5 mice (Fig.…”

“…Recent studies in our laboratory have used mice deficient in either Lrp5 or Lrp6 in osteoblasts to examine the contribution of each Wnt coreceptor to postnatal bone acquisition (6). Although both mutants exhibit the expected reduction in bone mineral density (Fig.…”

“…The Institutional Animal Care and Use Committee of the Johns Hopkins University approved all procedures involving mice. The generation of mice lacking Lrp5 (⌬Lrp5) and Lrp6 (⌬Lrp6) in osteoblasts was described previously (6). In brief, osteocalcin-Cre (Oc-Cre TG/ϩ ) mice (39) were crossed with mice in which the second exon of Lrp5 or Lrp6 is floxed.…”

“…In this pathway, low-density-lipoprotein (LDL)-related receptor 5 (Lrp5) and the closely related Lrp6 participate in the stabilization and activation of the transcription factor ␤-catenin by facilitating the interaction of Wnt ligands with frizzled receptors (3,4). Osteoblasts express all the components of the Wnt/␤-catenin pathway, and most have now been linked with bone development and maintenance in humans and mouse models (5)(6)(7). Mutations in the LRP5 gene, in particular, can result in premature and generalized osteoporosis as in the rare condition osteoporosis pseudoglioma (8) or a high-bone-mass phenotype (9,10) likely due to an increase in the number of mineralizing osteoblasts (11).…”

Macrophages of genetically characterized familial hypercholesterolaemia patients show up‐regulation of LDL‐receptor‐related proteins

“…In addition, the FH‐AT group had significantly higher LRP6 levels compared with their hypercholesterolaemic non‐FH controls. LRP6 is a protein with high homology to LRP5 and both receptors carry out redundant functions 62. Overall, LRP5 expression levels in PBL were significantly higher in FH patients ( N = 77) than in the non‐FH ( N = 46) (86.8 ± 2.3 versus 78.8 ± 2.8, P = 0.019).…”