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Matrix metalloproteinase-13 expression in IL-1β-treated chondrocytes by activation of the p38 MAPK/c-Fos/AP-1 and JAK/STAT pathways

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Abstract

Matrix metalloproteinase-13 (MMP-13, mammalian collagenase) degrades the cartilage matrix in pathological conditions such as osteoarthritis. Here, to establish the signaling pathway to MMP-13 induction, effects of mitogen-activated protein kinase (MAPK) pathway and the possibility of some other signaling pathways involved are investigated in interleukin-1β (IL-1β)-treated human chondrosarcoma cell line, SW1353 cells. IL-1β (10 ng/mL) treatment induced MMP-13 in SW1353 cells, with concomitant activation of nuclear factor-κB, activator protein-1 (AP-1) and MAPKs, including extracellular signal-regulated protein kinase, p38 MAPK and c-Jun N-terminal kinase. Among these MAPKs, only p38 MAPK inhibitor (SB203580) blocked MMP-13 induction and AP-1 activation in IL-1β-treated SW1353 cells. SB203580 also inhibited c-Fos translocation to the nucleus (but not c-Jun). Importantly, IL-1β treatment induced Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1/2 (STAT1/2) activation. The JAK2 inhibitor (AG490) blocked STAT1/2 activation as well as MMP-13 induction in IL-1β-treated SW1353 cells. STAT1/2 siRNA transfection also reduced MMP-13 expression levels. Thus, from the present study, it is concluded that p38 MAPK/c-Fos/AP-1 and JAK2/STAT1/2 are involved in MMP-13 induction of IL-1β-treated human chondrocytes, SW1353 cells. Blocking these signaling pathways may have chondroprotective effects in cartilage degeneration.

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References

  • Aikawa, Y., Morimoto, K., Yamamoto, T., Chaki, H., Hashiramoto, A., Narita, H., Hirono, S., and Shiozawa, S., Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1. Nat. Biotechnol., 26, 817–823 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Barksby, H. E., Hui, W., Wappler, I., Peters, H. H., Milner, J. M., Richards, C. D., Cawston, T. E., and Rowan, A. D., Interleukin-1 in combination with oncostatin M upregulates multiple genes in chondrocytes: implications for cartilage destruction and repair. Arthritis Rheum., 54, 540–550 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Behera, A. K., Thorpe, C. M., Kidder, J. M., Smith, W., Hildebrand, E., and Hu, L. T., Borrelia burgdorferi-induced expression of matrix metalloproteinases from human chondrocytes requires mitogen-activated protein kinase and janus kinase/signal transducer and activator of transcription signaling pathways. Infect. Immun., 72, 2864–2871 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Boileau, C., Pelletier, J. P., Tardif, G., Fahmi, H., Laufer, S., Lavigne, M., and Martel-Pelletier, J., The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway. Ann. Rheum. Dis., 64, 891–898(2005).

    Article  PubMed  CAS  Google Scholar 

  • Catterall, J. B., Carrère, S., Koshy, P. J., Degnan, B. A., Shingleton, W. D., Brinckerhoff, C. E., Rutter, J., Cawston, T. E., and Rowan, A. D., Synergistic induction of matrix metalloproteinase 1 by interleukin-1 and oncostatin M in human chondrocytes involved signal transducer and activation of transcription and activator protein 1 transcription factors via a novel mechanism. Arthritis Rheum., 44,2296–2310 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Cowell, S., Knäuper, V., Stewart, M. L., D’Ortho, M. P., Stanton, H., Hembry, R. M., López-Otín, C., Reynolds, J. J., and Murphy, G., Induction of matrix metalloproteinase activation cascades based on membrane-type 1 matrix metalloproteinase: associated activation of gelatinase A, gelatinase B and collagenase 3. Biochem. J., 331, 453–458 (1998).

    PubMed  CAS  Google Scholar 

  • Elliott, S., Hays, E., Mayor, M., Sporn, M., and Vincenti, M., The triterpenoid CDDO inhibits expression of matrix metalloproteinase-1, matrix metalloproteinase-13 and Bcl-3 in primary human chondrocytes. Arthritis Res. Ther., 5, R285–R291 (2003).

    Article  PubMed  CAS  Google Scholar 

  • El Mabrouk, M., Sylvester, J., and Zafarullah, M., Signaling pathways implicated in oncostatin M-induced aggrecanase-1 and matrix metalloproteinase-13 expression in human articular chondrocytes. Biochim. Biophys. Acta, 1773, 309–320 (2007).

    Article  PubMed  Google Scholar 

  • Fan, Z., Bau, B., Yang, H., Soeder, S., and Aigner, T., Freshly isolated osteoarthritic chondrocytes are catabolically more active than normal chondrocytes, but less responsive to catabolic stimulation with interleukin-1ß. Arthritis Rheum., 52, 136–143 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Fan, Z., Yang, H., Bau, B., Söder, S., and Aigner, T., Role of mitogen-activated protein kinases and NF-κB on IL-1β-induced effects on collagen type II, MMP-1 and 13 mRNA expression in normal articular human chondrocytes. Rheumatol. Int., 26, 900–903 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Gebauer, M., Saas, J., Sohler, F., Haag, J., Söder, S., Pieper, M., Bartnik, E., Beninga, J., Zimmer, R., and Aigner, T., Comparison of the chondrosarcoma cell line SW1353 with primary human adult articular chondrocytes with regard to their gene expression profile and reactivity to IL-1β. Osteoarthritis Cartilage, 13, 697–708 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Heinrich, P. C., Behrmann, I., Müller-Newen, G., Schaper, F., and Graeve, L., Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J., 334, 297–314 (1998).

    PubMed  CAS  Google Scholar 

  • Ho, L. J., Lin, L. C., Hung, L. F., Wang, S. J., Lee, C. H., Chang, D. M., Lai, J. H., and Tai, T. Y., Retinoic acid blocks pro-inflammatory cytokine-induced matrix metalloproteinase production by down-regulating JNK-AP-1 signaling in human chondrocytes. Biochem. Pharmacol., 70, 200–208 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Johnson, A. R., Pavlovsky, A. G., Ortwine, D. F., Prior, F., Man, C. F., Bornemeier, D. A., Banotai, C. A., Mueller, W. T., McConnell, P., Yan, C., Baragi, V., Lesch, C., Roark, W. H., Wilson, M., Datta, K., Guzman, R., Han, H. K., and Dyer, R. D., Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects. J. Biol. Chem., 282, 27781–27791 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Legendre, F., Bogdanowicz, P., Boumediene, K., and Pujol, J.-P., Role of interleukin 6 (IL-6)/IL-6R-induced signal transducers and activators of transcription and mitogen-activated protein kinase/extracellular signal-related kinase in upregulation of matrix metalloproteinase and ADAMTS gene expression in articular chondrocytes. J. Rheumatol., 32, 1307–1316 (2005).

    PubMed  Google Scholar 

  • Li, W. Q., Dehnade, F., and Zafarullah, M., Oncostatin Minduced matrix metalloproteinase and tissue inhibitor of mettaloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J. Immunol., 166, 3491–3498 (2001).

    PubMed  CAS  Google Scholar 

  • Liacini, A., Sylvester, J., Li, W. Q., and Zafarullah, M., Mithramycin downregulates proinflammatory cytokine-induced matrix metalloproteinase gene expression in articular chondrocytes. Arthritis Res. Ther., 7, R777–783 (2005).

    Article  PubMed  CAS  Google Scholar 

  • Mengshol, J. A., Vincenti, M. P., Coon, C. I., Barchowsky, A., and Brinckerhoff, C. E., Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c-Jun N-terminal kinase, and nuclear factor κB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum., 43, 801–811 (2000).

    Article  PubMed  CAS  Google Scholar 

  • Mengshol, J. A., Vincenti, M. P., and Brinckerhoff, C. E., IL-1 induces collagenase-3 (MMP-13) promoter activity in stably transfected chondrocytic cells: requirement for Runx-2 and activation by p38 MAPK and JNK pathways. Nucleic Acids Res., 29, 4361–4372 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Mitchell, P. G., Magna, H. A., Reeves, L. M., Lopresti-Morrow, L. L., Yocum, S. A., Rosner, P. J., Geoghegan, K. F., and Hambor, J. E., Cloning, expression, and type II collagenolytic activity of matrix metalloproteinase-13 from human osteoarthritic cartilage. J. Clin. Invest., 97, 761–768 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Mosmann, T., Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 65, 55–63 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Pei, Y., Harvey, A., Yu, X. P., Chandrasekhar, S., and Thirunavukkarasu, K., Differential regulation of cytokineinduced MMP-1 and MMP-13 expression by p38 kinase inhibitors in human chondrosarcoma cells: potential role of Runx2 in mediating p38 effects. Osteoarthritis Cartilage, 14, 749–758 (2006).

    Article  PubMed  Google Scholar 

  • Pelletier, J. P., McCollum, R., Cloutier, J. M., and Martel-Pelletier, J., Synthesis of metalloproteases and interleukin 6 (IL-6) in human osteoarthritic synovial membrane is an IL-1 mediated process. J. Rheumatol. Suppl., 43, 109–114 (1995).

    PubMed  CAS  Google Scholar 

  • Pfander, D., Heinz, N., Rothe, P., Carl, H. D., and Swoboda, B., Tenascin and aggrecan expression by articular chondrocytes is influenced by interleukin 1β: a possible explanation for the changes in matrix synthesis during osteoarthritis. Ann. Rheum. Dis., 63, 240–244 (2004).

    Article  PubMed  CAS  Google Scholar 

  • Rose-John, S., Scheller, J., Elson, G., and Jones, S. A., Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J. Leukoc. Biol., 80, 227–236 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Rowan, A. D., Koshy, P. J., Shingleton, W. D., Degnan, B. A., Heath, J. K., Vernallis, A. B., Spaull, J. R., Life, P. F., Hudson, K., and Cawston, T. E., Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis Rheum., 44, 1620–1632 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Saha, N., Moldovan, F., Tardif, G., Pelletier, J. P., Cloutier, J. M., and Martel-Pelletier, J., Interleukin-1ß-converting enzyme/caspase-1 in human osteoarthritic tissues: localization and role in the maturation of interleukin-1ß and interleukin-18. Arthritis Rheum., 42, 1577–1587 (1999).

    Article  PubMed  CAS  Google Scholar 

  • Senolt, L., Grigorian, M., Lukanidin, E., Simmen, B., Michel, B. A., Pavelka, K., Gay, R. E., Gay, S., and Neidhart, M., S100A4 is expressed at site of invasion in rheumatoid arthritis synovium and modulates production of matrix metalloproteinases. Ann. Rheum. Dis., 65, 1645–1648 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Takaishi, H., Kimura, T., Dalal, S., Okada, Y., and D’Armiento, J., Joint diseases and matrix metalloproteinases: a role for MMP-13. Curr. Pharm. Biotechnol., 9, 47–54 (2008).

    Article  PubMed  CAS  Google Scholar 

  • Vidal, A., Sabatini, M., Rolland-Valognes, G., Renard, P., Madelmont, J. C., and Mounetou, E., Synthesis and in vitro evaluation of targeted tetracycline derivatives: effects on inhibition of matrix metalloproteinases. Bioorg. Med. Chem., 15, 2368–2374 (2007).

    Article  PubMed  CAS  Google Scholar 

  • Vincenti, M. P. and Brinckerhoff, C. E., Early response genes induced in chondrocytes stimulated with the inflammatory cytokine interleukin-1β. Arthritis Res., 3, 381–388 (2001).

    Article  PubMed  CAS  Google Scholar 

  • Wada, Y., Shimada, K., Sugimoto, K., Kimura, T., and Ushiyama, S., Novel p38 mitogen-activated protein kinase inhibitor R-130823 protects cartilage by down-regulating matrix metalloproteinase-1, -13 and prostaglandin E2 production in human chondrocytes. Int. Immunopharmacol., 6, 144–155 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Wen, D., Nong, Y., Morgan, J. G., Gangurde, P., Bielecki, A., Dasilva, J., Keaveney, M., Cheng, H., Fraser, C., Schopf, L., Hepperle, M., Harriman, G., Jaffee, B. D., Ocain, T. D., and Xu, Y., A selective small molecule IκB kinase β inhibitor blocks nuclear factor κB-mediated inflammatory responses in human fibroblast-like synoviocytes, chondrocytes and mast cells. J. Pharmacol. Exp. Ther., 317, 989–1001 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Wimsey, S., Lien, C. F., Sharma, S., Brennan, P. A., Roach, H. I., Harper, G. D., and Górecki, D. C., Changes in immunolocalisation of beta-dystroglycan and specific degradative enzymes in the osteoarthritic synovium. Osteoarthritis Cartilage, 14, 1181–1188 (2006).

    Article  PubMed  CAS  Google Scholar 

  • Yammani, R. R., Long, D., and Loeser, R. F., Interleukin-7 stimulates secretion of S100A4 by activating the Jak/STAT signaling pathway in human articular chondrocytes. Arthritis Rheum., 60, 792–800 (2009).

    Article  PubMed  CAS  Google Scholar 

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  1. College of Pharmacy, Kangwon National University, Chunchon, 200-701, Korea

    Hyun Lim & Hyun Pyo Kim

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  1. Hyun Lim
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Correspondence to Hyun Pyo Kim.

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Lim, H., Kim, H.P. Matrix metalloproteinase-13 expression in IL-1β-treated chondrocytes by activation of the p38 MAPK/c-Fos/AP-1 and JAK/STAT pathways. Arch. Pharm. Res. 34, 109–117 (2011). https://doi.org/10.1007/s12272-011-0113-4

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