title: Dexamethasone enhances osteoclast formation synergistically with transforming growth factor-beta by stimulating the priming of osteoclast progenitors for differentiation into osteoclasts.
abstract: Long-term administration of glucocorticoids (GCs) causes osteoporosis with a rapid and severe bone loss and with a slow and prolonged bone disruption. Although the involvement of GCs in osteoblastic proliferation and differentiation has been studied extensively, their direct action on osteoclasts is still controversial and not conclusive. In this study, we investigated the direct participation of GCs in osteoclastogenesis. Dexamethasone (Dex) at <10(-8) M stimulated, but at >10(-7) M depressed, receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast formation synergistically with transforming growth factor-beta. The stimulatory action of Dex was restricted to the early phase of osteoclast differentiation and enhanced the priming of osteoclast progenitors (bone marrow-derived monocytes/macrophages) toward differentiation into cells of the osteoclast lineage. The osteoclast differentiation depending on RANKL requires the activation of NF-kappaB and AP-1, and the DNA binding of these transcription factors to their respective consensus cis-elements was enhanced by Dex, consistent with the stimulation of osteoclastogenesis. However, Dex did not affect the RANKL-induced signaling pathways such as the activation of IkappaB kinase followed by NF-kappaB nuclear translocation or the activation of JNK. On the other hand, Dex significantly decreased the endogenous production of interferon-beta, and this cytokine depressed the RANKL-elicited DNA binding of NF-kappaB and AP-1, as well as osteoclast formation. Thus, the down-regulation of inhibitory cytokines such as interferon-beta by Dex may allow the osteoclast progenitors to be freed from the suppression of osteoclastogenesis, resulting in an increased number of osteoclasts, as is observed in the early phase of GC-induced osteoporosis.
authors.affiliation: Department of Oral Anatomy, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takuma
authors.forename: Toshio
authors.initials: T
authors.lastname: Kaneda
authors.forename: Takuya
authors.initials: T
authors.lastname: Sato
authors.forename: Setsuo
authors.initials: S
authors.lastname: Ninomiya
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Kumegawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Hakeda
mesh_terms: D000135:Acid Phosphatase / Q000032:analysis; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002352:Carrier Proteins / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects*; D004247:DNA / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016899:Interferon-beta / Q000235:genetics / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000737:chemistry / Q000166:cytology*; D010024:Osteoporosis / Q000139:chemically induced; D053245:RANK Ligand; D012333:RNA, Messenger / Q000032:analysis; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects; D013050:Spectrometry, Fluorescence; D013234:Stem Cells / Q000737:chemistry / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D005938:Glucocorticoids; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D016899:Interferon-beta; D003907:Dexamethasone; D016173:Macrophage Colony-Stimulating Factor; D004247:DNA; D000135:Acid Phosphatase