title: Osteocyte-derived RANKL is a critical mediator of the increased bone resorption caused by dietary calcium deficiency.
abstract: Parathyroid hormone (PTH) excess stimulates bone resorption. This effect is associated with increased expression of the osteoclastogenic cytokine receptor activator of nuclear factor κB ligand (RANKL) in bone. However, several different cell types, including bone marrow stromal cells, osteocytes, and T lymphocytes, express both RANKL and the PTH receptor and it is unclear whether RANKL expression by any of these cell types is required for PTH-induced bone loss. Here we have used mice lacking the RANKL gene in osteocytes to determine whether RANKL produced by this cell type is required for the bone loss caused by secondary hyperparathyroidism induced by dietary calcium deficiency in adult mice. Thirty days of dietary calcium deficiency caused bone loss in control mice, but this effect was blunted in mice lacking RANKL in osteocytes. The increase in RANKL expression in bone and the increase in osteoclast number caused by dietary calcium deficiency were also blunted in mice lacking RANKL in osteocytes. These results demonstrate that RANKL produced by osteocytes contributes to the increased bone resorption and the bone loss caused by secondary hyperparathyroidism, strengthening the evidence that osteocytes are an important target cell for hormonal control of bone remodeling.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Jinhu
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Marilina
authors.initials: M
authors.lastname: Piemontese
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
authors.forename: Jeff D
authors.initials: JD
authors.lastname: Thostenson
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Central Arkansas Veterans Healthcare System, Little Rock, AR, USA. Electronic address: caobrien@uams.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000172:deficiency*; D002136:Calcium, Dietary / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D017353:Gene Deletion; D006980:Hyperthyroidism / Q000150:complications / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010011:Osteocytes / Q000378:metabolism* / Q000473:pathology*; D053245:RANK Ligand / Q000378:metabolism*
chemical_list: D002136:Calcium, Dietary; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D053245:RANK Ligand; C045073:Cre recombinase; D019426:Integrases; D002118:Calcium
keywords: Osteoclast; Osteocyte; Parathyroid hormone; RANKL