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Tissue Inhibitor of Matrix Metalloproteinase-1 Suppresses Apoptosis of Mouse Bone Marrow Stromal Cell Line MBA-1

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Abstract

We investigated the action of tissue inhibitor of metalloproteinase-1 (TIMP-1) on apoptosis and differentiation of mouse bone marrow stromal cell line MBA-1. TIMP-1 did not affect alkaline phosphatase (ALP) activity, suggesting that it is not involved in osteoblastic differentiation in MBA-1 cells. However, TIMP-1 inhibited MBA-1 apoptosis induced by serum deprivation in a dose-dependent manner. Our study also showed increased Bcl-2 protein expression and decreased Bax protein expression with TIMP-1 treatment. TIMP-1 decreased cytochrome c release and caspase-3 activation in MBA-1 cells. TIMP-1 activated phosphatidylinositol 3-kinase (PI3-kinase) and c-Jun N-terminal kinase (JNK), and the PI3-kinase inhibitor LY294002 or the JNK inhibitor SP600125 abolished its antiapoptotic activity. To investigate whether antiapoptotic action of TIMP-1 was mediated through its inhibition on MMP activities, we constructed mutant TIMP-1 by side-directed mutagenesis, which abolished the inhibitory activity of MMPs by deletion of Cys1 to Ala4. Wild-type TIMP-1 and mutant TIMP-1 expression plasmids were transfected in MBA-1 cells, and results showed that mutant TIMP-1 still protected the induced MBA-1 cell against apoptosis. These data suggest that TIMP-1 antiapoptotic actions are mediated via the PI3-kinase and JNK signaling pathways and independent of TIMP-1 inhibition of MMP activities.

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Acknowledgments

This work was supported by grant 30200322 from the China National Natural Scientific Foundation and special grant 200259 from the National Excellent Doctorate Dissertation.

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Authors and Affiliations

  1. Institute of Endocrinology and Metabolism, Second Xiangya Hospital of Central South University, 86 Middle Renmin Road, Changsha, Hunan, 410011, People’s Republic of China

    L.-J. Guo, X.-H. Luo, H. Xie, H.-D. Zhou, L.-Q. Yuan, M. Wang & E.-Y. Liao

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  1. L.-J. Guo
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  2. X.-H. Luo
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  3. H. Xie
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  4. H.-D. Zhou
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  5. L.-Q. Yuan
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  6. M. Wang
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  7. E.-Y. Liao
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Correspondence to E.-Y. Liao.

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L.-J. Guo and X.-H. Luo this authors contributed equally to this work.

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Guo, LJ., Luo, XH., Xie, H. et al. Tissue Inhibitor of Matrix Metalloproteinase-1 Suppresses Apoptosis of Mouse Bone Marrow Stromal Cell Line MBA-1. Calcif Tissue Int 78, 285–292 (2006). https://doi.org/10.1007/s00223-005-0092-x

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  • DOI: https://doi.org/10.1007/s00223-005-0092-x

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