title: 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.
authors.affiliation: Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Shihezi Medical Collage, Shihezi University, Xinjiang, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Li
authors.forename: Qiujuan
authors.initials: Q
authors.lastname: Xing
authors.forename: Bing
authors.initials: B
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Weishan
authors.initials: W
authors.lastname: Wang
authors.forename: Chenhui
authors.initials: C
authors.lastname: Shi
authors.forename: Janet L
authors.initials: JL
authors.lastname: Crane
authors.forename: Xu
authors.initials: X
authors.lastname: Cao
authors.forename: Mei
authors.initials: M
authors.lastname: Wan
mesh_terms: D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019426:Integrases / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
chemical_list: D045930:Anabolic Agents; D044385:GTP-Binding Protein alpha Subunits; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555476:Lrp6 protein, mouse; D010281:Parathyroid Hormone; D051176:beta Catenin; D017868:Cyclic AMP-Dependent Protein Kinases; C045073:Cre recombinase; D019426:Integrases
keywords: BONE REMODELING; LRP6; OSTEOBLAST APOPTOSIS; OSTEOBLAST DIFFERENTIATION; PTH