title: Cortical bone loss caused by glucocorticoid excess requires RANKL production by osteocytes and is associated with reduced OPG expression in mice.
abstract: Glucocorticoid excess is a major cause of low bone mass and fractures. Glucocorticoid administration decreases cortical thickness and increases cortical porosity in mice, and these changes are associated with increased osteoclast number at the endocortical surface. Receptor activator of NF-κB ligand (RANKL) produced by osteocytes is required for osteoclast formation in cancellous bone as well as the increase in cortical bone resorption caused by mechanical unloading or dietary calcium deficiency. However, whether osteocyte-derived RANKL also participates in the increase in bone resorption caused by glucocorticoid excess is unknown. To address this question, we examined the effects of prednisolone on cortical bone of mice lacking RANKL production in osteocytes. Prednisolone administration increased osteoclast number at the endocortical surface, increased cortical porosity, and reduced cortical thickness in control mice, but none of these effects occurred in mice lacking RANKL in osteocytes. Prednisolone administration did not alter RANKL mRNA abundance but did reduce osteoprotegerin (OPG) mRNA abundance in osteocyte-enriched cortical bone. Similarly, dexamethasone suppressed OPG but did not increase RANKL production in cortical bone organ cultures and primary osteoblasts. These results demonstrate that RANKL produced by osteocytes is required for the cortical bone loss caused by glucocorticoid excess but suggest that the changes in endocortical resorption are driven by reduced OPG rather than elevated RANKL expression.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.
authors.forename: Marilina
authors.initials: M
authors.lastname: Piemontese
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.
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, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fujiwara
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, Arkansas; and.
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, Arkansas; Central Arkansas Veterans Healthcare System, Little Rock, Arkansas caobrien@uams.edu.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000139:chemically induced / Q000235:genetics*; D002452:Cell Count; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000187:drug effects; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism*; D053244:Osteoprotegerin / Q000096:biosynthesis* / Q000235:genetics*; D016062:Porosity / Q000187:drug effects; D011239:Prednisolone / Q000494:pharmacology; D053245:RANK Ligand / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D053244:Osteoprotegerin; D053245:RANK Ligand; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D003907:Dexamethasone; D011239:Prednisolone
keywords: glucocorticoids; osteoclasts; osteocytes; osteoprotegerin; receptor activator of nuclear factor-κB ligand