Suppressive effect of dexamethasone on TIMP-1 production involves murine osteoblastic MC3T3-E1 cell apoptosis

被引:23
|
作者
Xie, Hui [1 ]
Tang, Ling-Li [2 ]
Luo, Xiang-Hang [1 ]
Wu, Xi-Yu [1 ]
Wu, Xian-Ping [1 ]
Zhou, Hou-De [1 ]
Yuan, Ling-Qing [1 ]
Liao, Er-Yuan [1 ]
机构
[1] Cent S Univ, Xiangya Hosp 2, Inst Endocrinol & Metab, Changsha 410011, Hunan, Peoples R China
[2] Cent S Univ, Xiangya Hosp 2, Dept Clin Lab, Changsha 410011, Hunan, Peoples R China
关键词
Dexamethasone; Tissue inhibitor of metalloproteinase-1; Apoptosis; Osteoblast; GLUCOCORTICOID-INDUCED OSTEOPOROSIS; TISSUE INHIBITOR; IN-VITRO; STEROID-HORMONES; BONE-FORMATION; B-CELLS; METALLOPROTEINASE-1; EXPRESSION; DIFFERENTIATION; PROLIFERATION;
D O I
10.1007/s00726-009-0325-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1145 / 1153
页数:9
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