title: Suppressive effect of dexamethasone on TIMP-1 production involves murine osteoblastic MC3T3-E1 cell apoptosis.
abstract: High dose glucocorticoid (GC) treatment induces osteoporosis partly via increasing osteoblast apoptosis. However, the mechanism of GC-induced apoptosis has not been fully elucidated. Osteoblast-derived tissue inhibitor of metalloproteinase-1 (TIMP-1) was recently reported to be involved in bone metabolism. Our previous study demonstrated that TIMP-1 suppressed apoptosis of the mouse bone marrow stromal cell line MBA-1 (pre-osteoblast) induced by serum deprivation. Therefore, we tested the effect of the GC dexamethasone (Dex) on TIMP-1 production in murine osteoblastic MC3T3-E1 cells and further determined whether this action is associated with Dex-induced osteoblast apoptosis. Dex decreased TIMP-1 production in MC3T3-E1 cells, and this effect was blocked by the glucocorticoid receptor (GR) antagonists, RU486 and RU40555. Recombinant TIMP-1 protein reduced caspase-3 activation and apoptosis induced by Dex in MC3T3-E1 cells. In addition, the pro-apoptotic effect of the Dex was augmented by suppression of TIMP-1 with siRNA. Furthermore, mutant TIMP-1, which has no inhibitory effects on MMPs, yet protects MC3T3-E1 cells against Dex-induced apoptosis. Our study demonstrates that Dex suppresses TIMP-1 production in osteoblasts through GR, and this effect is associated with its induction of osteoblast apoptosis. The anti-apoptotic action of TIMP-1 is independent of its inhibitory effects on MMPs activities. The decrease in TIMP-1 production caused by Dex may contribute to the mechanisms of Dex-induced bone loss.
authors.affiliation: Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Ling-Li
authors.initials: LL
authors.lastname: Tang
authors.forename: Xiang-Hang
authors.initials: XH
authors.lastname: Luo
authors.forename: Xi-Yu
authors.initials: XY
authors.lastname: Wu
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Wu
authors.forename: Hou-De
authors.initials: HD
authors.lastname: Zhou
authors.forename: Ling-Qing
authors.initials: LQ
authors.lastname: Yuan
authors.forename: Er-Yuan
authors.initials: EY
authors.lastname: Liao
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001862:Bone Resorption / Q000139:chemically induced / Q000517:prevention & control; D053148:Caspase 3 / Q000378:metabolism; D003907:Dexamethasone / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000633:toxicity*; D006727:Hormone Antagonists / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D050505:Mutant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D013997:Time Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D006727:Hormone Antagonists; D050505:Mutant Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; C075646:RU 40555; D015735:Mifepristone; D003907:Dexamethasone; D053148:Caspase 3; D020782:Matrix Metalloproteinases