Adrenergic stimulation of osteoclastogenesis mediated by expression of osteoclast differentiation factor in MC3T3-E1 osteoblast-like cells.
It is well known that adrenergic agonists efficiently activate beta-adrenoceptors on osteoblastic cells and can stimulate bone resorption in intact mouse calvaria. Recently, an osteoclastogenic factor of osteoblastic origin was found to be a novel tumor necrosis factor ligand family member and was termed osteoclast differentiation factor (ODF). Using a reverse transcription-polymerase chain reaction approach, we investigated the effect of epinephrine on mRNA levels of ODF and its decoy receptor, osteoclastogenesis inhibitory factor (OCIF), in MC3T3-E1 cells. Treatment with epinephrine (1 microM) rapidly increased ODF and OCIF mRNA levels, which peaked after 0.5 hr of treatment. Epinephrine (1 microM) also increased interleukin (IL)-6, IL-11, and cyclooxygenase (COX)-II mRNA levels, as well as increased prostaglandin E(2) (PGE(2)) accumulation in the culture medium. Treatment of the cells with IL-11 (10 ng/mL) or PGE(2) (1 microM) increased ODF and OCIF mRNA levels as observed with epinephrine. However, increases in ODF and OCIF mRNA levels by epinephrine were more rapid than those by IL-11, and were not influenced by NS-398 (100 microM; an inhibitor of COX-II), suggesting a direct effect of epinephrine on ODF and OCIF mRNA expressions as well as an indirect effect mediated by IL-11 and PGE(2) production. Epinephrine-induced increases in ODF and OCIF mRNA levels were inhibited by pretreatment with timolol (1 microM; beta-antagonist) and phentolamine (1 microM; alpha-antagonist), respectively. Furthermore, the formation of tartrate-resistant acid phosphatase-positive multinucleated cells from mouse bone marrow cells was stimulated by isoproterenol (0.1 to 10 microM) or epinephrine (0.1 to 10 microM). The action of isoproterenol, a beta-agonist, was clearly stronger than that of epinephrine, suggesting the importance of the physiological balance between ODF and OCIF productions for osteoclastogenesis. These findings suggest that beta-adrenergic stimulation induces not only IL-6, IL-11, and PGE(2) but also ODF expression in osteoblastic cells, leading to a stimulation of osteoclastogenesis.
Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, 464-8650, Nagoya, Japan.
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Takeuchi
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Tsuboi
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Arai
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Togari
D000322:Adrenergic Agonists / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor
D000322:Adrenergic Agonists; D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse