title: Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor.
abstract: Androgen deficiency in males leads to an increase in osteoclastic bone resorption and a progressive decrease in bone mineral density. In the current studies, we examined the ability of 5 alpha-dihydrotestosterone to suppress osteoclast formation induced by receptor activator of NF-kB ligand (RANKL) and macrophage-colony stimulating factor in vitro. 5 alpha-Dihydrotestosterone suppressed the differentiation of bone marrow monocytes into osteoclasts from both sham-operated and orchidectomized mice. Androgen deficiency also led to an increase in the number of hematopoietic precursors capable of forming osteoclasts and increased the relative responsiveness of these cells to androgens in vitro. Interestingly, E2 was as effective as 5 alpha-dihydrotestosterone in suppressing osteoclast formation in bone marrow monocytes from both sham and orchidectomized mice. As with bone marrow monocytes, 5 alpha-dihydrotestosterone also suppressed RANKL-induced osteoclast formation in the monocyte-macrophagic cell line RAW264.7. In RAW264.7 cells, androgens appear to block RANKL-induced osteoclast formation through selective regulation of c-JUN: Accordingly, 5 alpha-dihydrotestosterone suppressed RANKL-induced c-Jun N-terminal kinase activation and reduced c-Jun expression levels. These effects resulted in a reduction in RANKL-induced activator protein-1 DNA binding activity and a corresponding suppression in activator protein-1-mediated transcriptional activation. These studies indicate that both E and androgens can suppress osteoclast formation via a direct, stromal cell-independent action on osteoclast precursors to block key transcription factors such as c-Jun essential for osteoclast differentiation.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Huber
authors.forename: A C
authors.initials: AC
authors.lastname: Bendixen
authors.forename: P
authors.initials: P
authors.lastname: Pathrose
authors.forename: S
authors.initials: S
authors.lastname: Srivastava
authors.forename: K M
authors.initials: KM
authors.lastname: Dienger
authors.forename: N K
authors.initials: NK
authors.lastname: Shevde
authors.forename: J W
authors.initials: JW
authors.lastname: Pike
mesh_terms: D000728:Androgens / Q000172:deficiency / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002352:Carrier Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009919:Orchiectomy; D010010:Osteoclasts / Q000166:cytology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011944:Receptors, Androgen / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000728:Androgens; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011944:Receptors, Androgen; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases