Disruption of LRP6 in osteoblasts blunts the bone anabolic activity of PTH

Abstract

Mutations in low-density lipoprotein receptor-related protein 6 (LRP6) are associated with human skeletal disorders. LRP6 is required for parathyroid hormone (PTH)-stimulated signaling pathways in osteoblasts. We investigated whether LRP6 in osteoblasts directly regulates bone remodeling and mediates the bone anabolic effects of PTH by specifically deleting LRP6 in mature osteoblasts in mice (LRP6 KO). Three-month-old LRP6 KO mice had a significant reduction in bone mass in the femora secondary spongiosa relative to their wild-type littermates, whereas marginal changes were found in femoral tissue of 1-month-old LRP6 KO mice. The remodeling area of the 3-month-old LRP6 KO mice showed a decreased bone formation rate as detected by Goldner's Trichrome staining and calcein double labeling. Bone histomorphometric and immumohistochemical analysis revealed a reduction in osteoblasts but little change in the numbers of osteoclasts and osteoprogenitors/osteoblast precursors in LRP6 KO mice compared with wild-type littermates. In addition, the percentage of the apoptotic osteoblasts on the bone surface was higher in LRP6 KO mice compared with wild-type littermates. Intermittent injection of PTH had no effect on bone mass or osteoblastic bone formation in either trabecular and cortical bone in LRP6 KO mice, whereas all were enhanced in wild-type littermates. Additionally, the anti-apoptotic effect of PTH on osteoblasts in LRP6 KO mice was less significant compared with wild-type mice. Therefore, our findings demonstrate that LRP6 in osteoblasts is essential for osteoblastic differentiation during bone remodeling and the anabolic effects of PTH.