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

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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.

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Acknowledgments

This work was supported by grants 30572078, 30600661 and 30872708 from the China National Natural Scientific Foundation, a grant from the Chinese National Key Basic Research Project (2006CB503808), and the Post-Doctorate Science Foundation of the People’s Republic of China (20070410995), the Post-Doctorate Scientific Research Special-Purpose Project of Hunan Province (2008RS4012).

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Authors and Affiliations

  1. Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, 139 Middle Renmin Road, Changsha, Hunan, 410011, People’s Republic of China

    Hui Xie, Xiang-Hang Luo, Xi-Yu Wu, Xian-Ping Wu, Hou-De Zhou, Ling-Qing Yuan & Er-Yuan Liao

  2. Department of Clinical Laboratory, Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, People’s Republic of China

    Ling-Li Tang

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  1. Hui Xie
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Correspondence to Er-Yuan Liao.

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Hui Xie and Ling-Li Tang have contributed equally to this work.

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Xie, H., Tang, LL., Luo, XH. et al. Suppressive effect of dexamethasone on TIMP-1 production involves murine osteoblastic MC3T3-E1 cell apoptosis. Amino Acids 38, 1145–1153 (2010). https://doi.org/10.1007/s00726-009-0325-9

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