Bone morphogenetic protein-2 enhances osteoclast formation mediated by interleukin-1alpha through upregulation of osteoclast differentiation factor and cyclooxygenase-2.
Bone morphogenic protein-2 (BMP-2) is a member of the transforming growth factor beta (TGF-beta) superfamily. While BMP-2 is capable of inducing bone formation ectopically, little is known about its role on osteoclastogenesis. In this study, we examined the effect of BMP-2 on osteoclast-like multinucleated cell (OCL) formation in cocultures of osteoblast-like cells and hematopoietic cells of bone marrow origin. BMP-2 alone did not stimulate OCL formation in this culture system; however, it strongly enhanced OCL formation in a dose-dependent fashion in the presence of interleukin-1alpha (IL-1alpha). Western blot analysis showed that a simultaneous addition of BMP-2 and IL-1alpha synergistically enhanced cyclooxygenase-2 (COX-2) expression in osteoblast-like cells. Moreover, Northern blot analysis revealed that the level of osteoclast differentiation factor (ODF) mRNA increased by treatment with BMP-2 and IL-1alpha in osteoblast-like cells. It is noted that BMP-2 alone did cause an increase in the expression of both COX-2 and ODF genes. The stimulatory effect of BMP-2 was abolished by adding nonsteroidal anti-inflammatory drugs, such as indomethacin and a selective COX-2 inhibitor NS-398. Addition of NS-398 inhibited the expression of the ODF gene in osteoblast-like cells treated with BMP-2 and IL-1alpha. These results indicated that the combination of BMP-2 and IL-1alpha stimulated osteoblast-like cells to elevate the expression of both COX-2 and ODF genes, resulting in an enhanced OCL formation. Since BMP-2 alone induced the expression of COX-2 and ODF genes in osteoblast-like cells, it appears to be one of the regulating factors of osteoclastogenesis.
Koide
M
M
Department of Oral Science, National Institute of Infectious Diseases, Tokyo, Japan.
Murase
Y
Y
Yamato
K
K
Noguchi
T
T
Okahashi
N
N
Nishihara
T
T
D028341:Activins; D000818:Animals; D001846:Bone Development / Q000187:drug effects; D001854:Bone Marrow Cells; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D007213:Indomethacin / Q000494:pharmacology; D007265:Inhibins / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009578:Nitrobenzenes / Q000494:pharmacology; D010010:Osteoclasts / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D015854:Up-Regulation / Q000235:genetics
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D009578:Nitrobenzenes; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D013449:Sulfonamides; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D016212:Transforming Growth Factor beta; D028341:Activins; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D007265:Inhibins; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin