title: Inhibitory effect of vitamin K(2) on interleukin-1beta-stimulated proliferation of human osteoblasts.
abstract: The effect of the proinflammatory cytokine interleukin (IL)-1beta on the cellular proliferation of human osteoblastic cells (SaM-1) and osteosarcoma-derived cells (SaOS-2, HOS, and MG-63) was examined. IL-1beta stimulated the proliferation of SaM-1 and MG-63 cells, but had no effect on that of SaOS-2 or HOS cells. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, the mRNA expression of IL-1 receptor type I (IL-1R1) was detected in SaM-1 and MG-63 cells consistently, but not in SaOS-2 or HOS cells in the proliferative stage. Neither the decoy inhibitory IL-1 receptor type II (IL-1R2) nor IL-1R antagonist mRNA was detected in any of the cell lines, suggesting that IL-1beta stimulated proliferation via IL-1R1. The IL-1beta -stimulated proliferation was inhibited by the MAPK kinase (MEK) inhibitor PD98059 but not by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 or the cyclooxygenase-2 specific inhibitor NS-398, suggesting that IL-1beta stimulated proliferation via MEK, without affecting prostaglandin E(2) synthesis. IL-1beta stimulated cellular proliferation but inhibited the synthesis of osteocalcin containing gamma-carboxylated glutamic acid (Gla-OSCAL). Both the increased proliferation and decreased Gla-OSCAL synthesis were suppressed by vitamin K(2) (VK(2)), which is a cofactor for gamma-carboxylase. Furthermore, the inhibitory effect of VK(2) on IL-1beta -stimulated proliferation was suppressed by warfarin. However, rifampicin the nuclear receptor steroid and xenobiotic receptor (SXR) ligand had no effect of IL-beta, suggesting that IL-1beta is involved in VK(2) dependent gamma-calboxylation but not SXR-activation. These results suggest that IL-1beta stimulated cellular proliferation via MEK and inhibited Gla-OSCAL synthesis, which were both inhibited by VK(2) via gamma-carboxylation.
authors.affiliation: Department of Pharmacology, School of Dentistry, Aichi-Gakuin University, 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Matsuda
authors.forename: Ayami
authors.initials: A
authors.lastname: Kondo
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tsunashima
authors.forename: Akifumi
authors.initials: A
authors.lastname: Togari
mesh_terms: D000328:Adult; D000925:Anticoagulants; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors; D005419:Flavonoids / Q000494:pharmacology; D018698:Glutamic Acid / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009578:Nitrobenzenes / Q000494:pharmacology; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000378:metabolism*; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism; D000077297:Pregnane X Receptor; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012293:Rifampin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014812:Vitamin K / Q000494:pharmacology*; D014815:Vitamins / Q000494:pharmacology*; D014859:Warfarin / Q000494:pharmacology; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
chemical_list: D000925:Anticoagulants; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D007375:Interleukin-1; D053583:Interleukin-1beta; D009578:Nitrobenzenes; D000077297:Pregnane X Receptor; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D011987:Receptors, Steroid; D013449:Sulfonamides; D014815:Vitamins; D015675:Osteocalcin; D014812:Vitamin K; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D018698:Glutamic Acid; D014859:Warfarin; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D012293:Rifampin