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Suppressive effect of dexamethasone on TIMP-1 production involves murine osteoblastic MC3T3-E1 cell apoptosis
Hui Xie1, Ling-Li Tang, Xiang-Hang Luo
1Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People's Republic of China.
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.
Insights
High-dose glucocorticoids (GCs) reduce tissue inhibitor of metalloproteinase-1 (TIMP-1) in osteoblasts, increasing apoptosis and contributing to bone loss. TIMP-1 protects osteoblasts from GC-induced cell death independently of MMP inhibition.
Area of Science:
- Biochemistry
- Cell Biology
- Endocrinology
Background:
- High-dose glucocorticoid (GC) therapy can induce osteoporosis by promoting osteoblast apoptosis.
- The precise mechanisms underlying GC-induced osteoblast apoptosis remain incompletely understood.
- Tissue inhibitor of metalloproteinase-1 (TIMP-1), produced by osteoblasts, plays a role in bone metabolism and has shown anti-apoptotic effects in previous studies.
Purpose of the Study:
- To investigate the effect of dexamethasone (Dex), a GC, on TIMP-1 production in osteoblasts.
- To determine if Dex-induced changes in TIMP-1 are linked to osteoblast apoptosis.
- To elucidate the role of TIMP-1's matrix metalloproteinase (MMP)-inhibitory activity in its protective effects against GC-induced apoptosis.
Main Methods:
- Murine osteoblastic MC3T3-E1 cells were treated with Dex.
- The impact of Dex on TIMP-1 production was assessed, along with the effects of glucocorticoid receptor (GR) antagonists (RU486, RU40555).
- Recombinant TIMP-1 protein and siRNA-mediated TIMP-1 knockdown were used to evaluate TIMP-1's role in apoptosis. Mutant TIMP-1 was also employed to assess MMP-independent effects.
Main Results:
- Dexamethasone significantly decreased TIMP-1 production in MC3T3-E1 cells, an effect blocked by GR antagonists.
- Recombinant TIMP-1 protein administration reduced caspase-3 activation and Dex-induced apoptosis.
- TIMP-1 suppression via siRNA exacerbated Dex-induced apoptosis, while MMP-inactive mutant TIMP-1 still protected cells from apoptosis.
Conclusions:
- Dexamethasone suppresses osteoblast TIMP-1 production via the glucocorticoid receptor pathway.
- This reduction in TIMP-1 contributes to GC-induced osteoblast apoptosis.
- The anti-apoptotic function of TIMP-1 in this context is independent of its MMP inhibitory activity, suggesting a direct role in cell survival.
