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Matrix metalloproteinase 9 expression: new regulatory elements

  • Published:
Journal of Ocular Biology, Diseases, and Informatics

Abstract

Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma. Here, we investigated the role of 3′-untranslated regions (3′-UTR) and microRNAs in MMP-9 regulation. We used in vitro mutagenesis and Luc reporter system to identify regulatory elements in the 3′-UTR of MMP-9. microRNAs were analyzed by qRT-PCR, and their role was investigated with inhibitors and mimics. We identified targets for miRNAs in 3′-UTR of MMP-9 involved in the regulation of MMP-9 expression. We then isolated miRNAs from the optic nerve A7 astrocytes and 293 T cells and confirmed the role of mi340 in the regulation using specific inhibitors and mimics. The results obtained show a new miRNA-mediated mechanism of MMP-9 expression regulation.

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References

  1. Sommer A. Intraocular pressure and glaucoma. Am J Ophthalmol. 1989;107:186–8.

    PubMed  CAS  Google Scholar 

  2. Garcia-Valenzuela E, Shareef S, Walsh J, Sharma SC. Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 1995;61:33–44.

    Article  PubMed  CAS  Google Scholar 

  3. Kerrigan L, Zack D, Quigley H, et al. TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997;115:1031–5.

    PubMed  CAS  Google Scholar 

  4. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Investig Ophthalmol Vis Sci. 1995;36:774–86.

    CAS  Google Scholar 

  5. Vu TH, Werb Z. Matrix metalloproteinases: effectors of development and normal physiology. Genes Dev. 2000;14:2123–33.

    Article  PubMed  CAS  Google Scholar 

  6. Agapova OA, Ricard CS, Salvador-Silva M, Hernandez MR. Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human optic nerve head astrocytes. Glia. 2001;33:205–16.

    Article  PubMed  CAS  Google Scholar 

  7. Yan X, Tezel G, Wax MB, Edward DP. Matrix metalloproteinases and tumor necrosis factor alpha in glaucomatous optic nerve head. Arch Ophthalmol. 2000;18:666–73.

    Google Scholar 

  8. Morgan JE. Optic nerve head structure in glaucoma: astrocytes as mediators of axonal damage. Eye (Lond). 2000;14:437–44.

    Google Scholar 

  9. Hernandez MR. The optic nerve head in glaucoma: role of astrocytes in tissue remodeling. Prog Retin Eye Res. 2000;19:297–321.

    Article  PubMed  CAS  Google Scholar 

  10. Chintala SK, Zhang X, Austin JS, Fini ME. Deficiency in matrix metalloproteinase gelatinase B (MMP-9) protects against retinal ganglion cell death after optic nerve ligation. J Biol Chem. 2002;277:47461–8.

    Article  PubMed  CAS  Google Scholar 

  11. Zhang X, Chintala SK. Influence of interleukin-1 beta induction and mitogen-activated protein kinase phosphorylation on optic nerve ligation-induced matrix metalloproteinase-9 activation in the retina. Exp Eye Res. 2004;78:849–60.

    Article  PubMed  CAS  Google Scholar 

  12. Manabe S, Gu Z, Lipton S. Activation of matrix metalloproteinase-9 via neuronal nitric oxide synthase contributes to NMDA-induced retinal ganglion cell death. Investig Ophthalmol Vis Sci. 2005;46:4747–53.

    Article  Google Scholar 

  13. Cong Y, Guo X, Liu X, Cao D, Jia X, Xiao X, et al. Association of the single nucleotide polymorphisms in the extracellular matrix metalloprotease-9 gene with PACG in southern China. Mol Vis. 2009;15:1412–7.

    PubMed  CAS  Google Scholar 

  14. Guo L, Moss SE, Alexander RA, Ali RR, Fitzke FW, Cordeiro MF. Retinal ganglion cell apoptosis in glaucoma is related to intraocular pressure and iop-induced effects on extracellular matrix. Investig Ophthalmol Vis Sci. 2005;46:175–82.

    Article  Google Scholar 

  15. Mozaffarieh M, Flammer J. Is there more to glaucoma treatment than lowering IOP? Surv Ophthalmol. 2007;52:S174–9.

    Article  PubMed  Google Scholar 

  16. Golubnitschaja-Labudova O, Liu R, Decker C, Zhu P, Haefliger IO, Flammer J. Altered gene expression in lymphocytes of patients with normal-tension glaucoma. Curr Eye Res. 2000;21:867–76.

    Article  PubMed  CAS  Google Scholar 

  17. Rivera S, Ogier C, Jourquin J, et al. Gelatinase B and TIMP-1 are regulated in a cell- and time-dependent manner in association with neuronal death and glial reactivity after global forebrain ischemia. Eur J Neurosci. 2002;15:19–32.

    Article  PubMed  Google Scholar 

  18. Vaillant C, Meissirel C, Mutin M, Belin MF, Lund LR, Thomasset N. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellum. Mol Cell Neurosci. 2003;24:395–408.

    Article  PubMed  CAS  Google Scholar 

  19. Chow AK, Cena J, Schulz R. Acute actions and novel targets of matrix metalloproteinases in the heart and vasculature. Br J Pharmacol. 2007;152:189–205.

    Article  PubMed  CAS  Google Scholar 

  20. Lindeman JH, Abdul-Hussien H, van Bockel JH, Wolterbeek R, Kleemann R. Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm. doxycycline selectively depletes aortic wall neutrophils and cytotoxic t cells. Circulation. 2009;119:2209–16.

    Article  PubMed  CAS  Google Scholar 

  21. Muroski ME, Roycik MD, Newcomer RG, Van den Steen PE, Opdenakker G, Monroe HR, et al. Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis. Curr Pharm Biotechnol. 2008;9:34–46.

    Article  PubMed  CAS  Google Scholar 

  22. Nothnick WB. Novel targets for the treatment of endometriosis. Expert Opin Ther Targets. 2004;8:459–71.

    Article  PubMed  CAS  Google Scholar 

  23. Geller HM, Dubois-Dalcq M. Antigenic and functional characterization of a rat central nervous system-derived cell line immortalized by a retroviral vector. J Cell Biol. 1988;107:1977–86.

    Article  PubMed  CAS  Google Scholar 

  24. Surgucheva I, Surguchov. γ-Synuclein: cell-type specific promoter activity and binding to transcription factors. J Mol Neurosci. 2008;35:267–71.

    Article  PubMed  CAS  Google Scholar 

  25. Barreau C, Paillard L, Osborne HB. AU-rich elements and associated factors: are there unifying principles? Nucleic Acids Res. 2006;33:7138–50.

    Article  PubMed  Google Scholar 

  26. Akool el S, Kleinert H, Hamada FM, Abdelwahab MH, Förstermann U, Pfeilschifter J, et al. Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol Cell Biol. 2003;23:4901–16.

    Article  Google Scholar 

  27. Krek A, Grun D, Poy MN, Wolf R, Rosenberg L, Epstein EJ, et al. Combinatorial microRNA target predictions. Nat Genet. 2005;37:495–500.

    Article  PubMed  CAS  Google Scholar 

  28. Betel D, Wilson M, Gabow A, Marks DS, Sander C. The microRNA.org resource: targets and expression. Nucleic Acids Res. 2008;36:D149–53.

    Article  PubMed  CAS  Google Scholar 

  29. Brennecke J, Stark A, Russell RB, Cohen SM. Principles of micro-RNA-target recognition. PLoS Biol. 2005;3:e85.

    Article  PubMed  Google Scholar 

  30. Mali RS, Cheng M, Chintala SK. Intravitreous injection of a membrane depolarization agent causes retinal degeneration via matrix metalloproteinase-9. Investig Ophthalmol Vis Sci. 2005;46:2125–32.

    Article  Google Scholar 

  31. Ganea E, Trifan M, Laslo AC, Putina G, Cristescu C. Matrix metalloproteinases: useful and deleterious. Biochem Soc Trans. 2007;35:689–91.

    Article  PubMed  CAS  Google Scholar 

  32. Sivak JM, West-Mays JA, Yee A, Williams T, Fini ME. Transcription factors Pax6 and AP-2alpha interact to coordinate corneal epithelial repair by controlling expression of matrix metalloproteinase gelatinase B. Mol Cell Biol. 2004;24:245–57.

    Article  PubMed  CAS  Google Scholar 

  33. Eberhardt W, Doller A, Akool el S, Pfeilschifter J. Modulation of mRNA stability as a novel therapeutic approach. Pharmacol Ther. 2007;114:56–73.

    Article  PubMed  CAS  Google Scholar 

  34. Fähling M, Steege A, Perlewitz A, Nafz B, Mrowka R, Persson PB, et al. Role of nucleolin in posttranscriptional control of MMP-9 expression. Biochim Biophys Acta. 2005;1731:32–40.

    PubMed  Google Scholar 

  35. Jespersen C, Doller A, Akool el-S, Bachmann M, Müller R, Gutwein P, et al. Molecular mechanisms of nitric oxide-dependent inhibition of TPA-induced matrix metalloproteinase-9 (MMP-9) in MCF-7 cells. J Cell Physiol. 2009;219:276–87.

    Article  PubMed  CAS  Google Scholar 

  36. Fingleton B. Matrix metalloproteinases as valid clinical targets. Curr Pharm Des. 2007;13:333–46.

    Article  PubMed  CAS  Google Scholar 

  37. Seki M, Soussou W, Manabe S, Lipton SA. Protection of retinal ganglion cells by caspase substrate-binding peptide IQACRG from N-methyl-d-aspartate receptor-mediated excitotoxicity. Investig Ophthalmol Vis Sci. 2010;51:1198–207.

    Article  Google Scholar 

  38. Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, et al. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci. 2005;25:6401–8.

    Article  PubMed  CAS  Google Scholar 

  39. Makeyev EV, Maniatis T. Multilevel regulation of gene expression by microRNAs. Science. 2008;319:1789–90.

    Article  PubMed  CAS  Google Scholar 

  40. Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, et al. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci USA. 2008;105:5874–8.

    Article  PubMed  CAS  Google Scholar 

  41. Boren T, Xiong Y, Hakam A, Wenham R, Apte S, Chan G, et al. MicroRNAs and their target messenger RNAs associated with ovarian cancer response to chemotherapy. Gynecol Oncol. 2009;113:249–55.

    Article  PubMed  CAS  Google Scholar 

  42. Georgiadis A, Tschernutter M, Bainbridge JW, Robbie SJ, McIntosh J, Nathwani AC, et al. AAV-mediated knockdown of Peripherin-2 in vivo using miRNA-based hairpins. Gene Ther. 2010;17:486–93.

    Article  PubMed  CAS  Google Scholar 

  43. Luna C, Li G, Qiu J, Epstein DL, Gonzalez P. Role of miR-29b on the regulation of the extracellular matrix in human trabecular meshwork cells under chronic oxidative stress. Mol Vis. 2009;15:2488–97.

    PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by VA Merit review grant and The Glaucoma Foundation grant.

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Correspondence to Andrei Surguchov.

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Surgucheva, I., Chidambaram, K., Willoughby, D.A. et al. Matrix metalloproteinase 9 expression: new regulatory elements. j ocul biol dis inform 3, 41–52 (2010). https://doi.org/10.1007/s12177-010-9054-2

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  • DOI: https://doi.org/10.1007/s12177-010-9054-2

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