Skip to main content

Advertisement

SpringerLink
Log in

IL-6 upregulates a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2) in human osteosarcoma cells mediated by JNK pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

ADAMTS-2 and ADAMTS-3 (a disintegrin and metalloproteinase with thrombospondin type 1 motif 2) belong to the procollagen aminoproteinase subfamily of ADAMTS proteases. They play crucial roles in the collagen metabolism. To understand the regulation of ADAMTS-2 gene expression in osteoblastic cells, we have cloned a functional 760 bp of human ADAMTS-2 promoter. Sequence analysis of the ADAMTS-2 promoter region showed the absence of a TATA box, but identified a GC box, a CpG island, several GAGA boxes and several transcriptional factor binding sites, which may be valuable in the regulation of ADAMTS-2 transcription. We also elucidated that Interleukin 6 (IL-6) increases ADAMTS-2 and ADAMTS-3 mRNA and protein levels in different osteosarcoma cell lines namely, MG-63 and Saos-2. IL-6 also increases the transcriptional activation of the ADAMTS-2 gene promoter. Pathway inhibition studies revealed that ADAMTS-2 upregulation by IL-6 was mediated by JNK pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R (1995) Toward a molecular understanding of skeletal development. Cell 80(3):371–378

    Article  CAS  PubMed  Google Scholar 

  2. Pfeilschifter J, Wolf O, Naumann A, Minne HW, Mundy GR, Ziegler R (1990) Chemotactic response of osteoblast like cells to transforming growth factor beta. J Bone Miner Res 5(8):825–830

    Article  CAS  PubMed  Google Scholar 

  3. Yamagiwa H, Tokunaga K, Hayami T, Hatano H, Uchida M, Endo N et al (1999) Expression of metalloproteinase-13 (collagenase-3) is induced during fracture healing in mice. Bone 25(2):197–203

    Article  CAS  PubMed  Google Scholar 

  4. Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC et al (2001) Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J Bone Miner Res 16(10):1739–1746

    Article  CAS  PubMed  Google Scholar 

  5. Bord S, Horner A, Hembry RM, Compston JE (1998) Stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) expression in developing human bone: potential roles in skeletal development. Bone 23(1):7–12

    Article  CAS  PubMed  Google Scholar 

  6. Knauper V, Will H, Lopez-Otin C, Smith B, Atkinson SJ, Stanton H et al (1996) Cellular mechanisms for human procollagenase-3 (MMP-13) activation: evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. J Biol Chem 271(29):17124–17131

    Article  CAS  PubMed  Google Scholar 

  7. Hernandez-Barrantes S, Toth M, Bernardo MM, Yurkova M, Gervasi Y, Raz Y et al (2000) Binding of active (57 kDa) membrane type 1-matrix metalloproteinase (MT1-MMP) to tissue inhibitor of metalloprotei-nase (TIMP)-2 regulates MT1-MMP processing and pro-MMP-2 activation. J Biol Chem 275:12080–120089

    Article  CAS  PubMed  Google Scholar 

  8. Filanti C, Dickson GR, Di Martino D, Ulivi V, Sanguineti C, Romano P et al (2000) The expression of metalloproteinase-2, -9, and -14 and of tissue inhibitors- 1 and -2 is developmentally modulated during osteogenesis in vitro, the mature osteoblastic phenotype expressing metalloproteinase-14. J Bone Miner Res 15:2154–2168

    Article  CAS  PubMed  Google Scholar 

  9. Inoue D, Reid M, Lum L, Kratzschmar J, Weskamp G, Myung YM et al (1998) Cloning and initial characterization of mouse meltrin beta and analysis of the expression of four metalloprotease-disintegrins in bone cells. J Biol Chem 273:4180–4187

    Article  CAS  PubMed  Google Scholar 

  10. Lind T, McKie N, Racey SN, Wendel M, Birch MA (2005) The hyalectan degrading ADAMTS-1 enzyme is expressed by osteoblasts and up-regulated at regions of new bone formation. Bone 36:408–417

    Article  CAS  PubMed  Google Scholar 

  11. Salter RC, Ashlin TG, Kwan AP, Ramji DP (2010) ADAMTS proteases: key roles in atherosclerosis? J Mol Med (Berl) 88(12):1203–1211

    Article  CAS  Google Scholar 

  12. Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lopez-Otin C (2002) Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Genes 283:49–62

    CAS  Google Scholar 

  13. Miles RR, Sluka JP, Halladay DL, Santerre RF, Hale LV, Bloem L et al (2000) ADAMTS-1: a cellular disintegrin and metalloprotease with thrombospondin motifs is a target for parathyroid hormone in bone. Endocrinology 141:4533–4542

    Article  CAS  PubMed  Google Scholar 

  14. Porter S, Clark IM, Kevorkian L, Edwards DR (2005) The ADAMTS metalloproteinases. J Biochem 386:15–27

    Article  CAS  Google Scholar 

  15. Tang BL (2001) ADAMTS: a novel family of extracellular matrixproteases. Int J Biochem Cell Biol 33(1):33–44

    Article  CAS  PubMed  Google Scholar 

  16. Kishimoto T (2005) Interleukin-6: from basic science to medicine—40 years in immunology. Annu Rev Immunol 23:1–21

    Article  CAS  PubMed  Google Scholar 

  17. Bellido T, Stahl N, Farruggella TJ et al (1996) Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neu-rotrophic factor in bone marrow stromal/osteoblastic cells. J Clin Invest 97(2):431–437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Taguchi Y, Yamamoto M, Yamate T et al (1998) Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage. Proc Assoc Am Phys 110(6):559–574

    CAS  PubMed  Google Scholar 

  19. Franchimont N, Gangji V, Durant D et al (1997) Interleukin-6 with its soluble receptor enhances the expression of insulin-like growth factor-I in osteoblasts. Endocrinology 138(12):5248–5255

    CAS  PubMed  Google Scholar 

  20. Yeh LC, Zavala MC, Lee JC (2002) Osteogenic protein-1 and interleukin-6 with its soluble receptor synergistically stimulate rat osteoblastic cell differentiation. J Cell Physiol 190(3):322–331

    Article  CAS  PubMed  Google Scholar 

  21. Li Y, Bäckesjö CM, Haldosén LA et al (2008) IL-6 receptor expression and IL-6 effects change during osteoblast differentiation. Cytokine 43(2):165–173

    Article  CAS  PubMed  Google Scholar 

  22. Malaval L, Liu F, Vernallis AB, Aubin JE (2005) GP130/OSMR is the only LIF/IL-6 familyreceptor complex to promote osteoblast differentiation of calvaria progenitors. J Cell Physiol 204(2):585–593

    Article  CAS  PubMed  Google Scholar 

  23. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G, Schaper F (2003) Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 374(1):1–20

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Mimata Y, Kamataki A, Oikawa S, Murakami K, Uzuki M, Shimamura T, Sawai T (2012) Interleukin-6 upregulates expression of ADAMTS-4 in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Int J Rheum Dis 15(1):36–44

    Article  CAS  PubMed  Google Scholar 

  25. Cartharius K, Frech K, Grote K, Klocke B, Haltmeier M, Klingenhoff A et al (2005) MatInspector and beyond: promoter analysis based on transcription factor binding sites. Bioinformatics 21:2933–2942

    Article  CAS  PubMed  Google Scholar 

  26. Yildirim H, Kockar F (2009) TGF-beta upregulates tumor-associated carbonic anhydrase IX gene expression in Hep3B cells. Cell Biol Int 33(9):1002–1007

    Article  CAS  PubMed  Google Scholar 

  27. Kockar FT, Foka P, Hughes TR, Kousteni S, Ramji DP (2001) Analysis of the Xenopus laevis CCAAT-enhancer binding protein alpha gene promoter demonstrates species-specific differences in the mechanisms for both auto-activation and regulation by Sp1. Nucleic Acids Res 29(2):362–372

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−DeltaDeltaC(T)) method. Methods 25(4):402–408

    Article  CAS  PubMed  Google Scholar 

  29. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  30. Hughes TR, Tengku-Muhammad TS, Irvine SA, Ramji DP (2002) A novel role of Sp1 and Sp3 in the interferon-g-mediated suppression of macrophage lipoprotein lipase gene transcription. J Biol Chem 277:11097–11106

    Article  CAS  PubMed  Google Scholar 

  31. Eliceiri K, Rueden C (2005) Tools for visualizing multidimensional images from living specimens. Photochem Photobiol 81(5):1116–1122

    Article  CAS  PubMed  Google Scholar 

  32. Hatipoglu OF, Hirohata S, Cilek MZ, Ogawa H, Miyoshi T, Obika M, Demircan K, Shinohata R, Kusachi S, Ninomiya Y (2009) ADAMTS1 is a unique hypoxic early response gene expressed by endothelial cells. J Biol Chem 284(24):16325–16333

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Kari M, Doyle H, Russell DL, Sriraman V (2004) Coordinate transcription of the ADAMTS-1 gene by luteinizing hormone and progesterone receptor. Mol Endocrinol 18(10):2463–2478

    Article  Google Scholar 

  34. Mizui Y, Yamazaki K, Kuboi Y, Sagane K, Tanaka I (2000) Characterization of the 5-flanking region of human aggrecanase-1 (ADAMTS4) gene. Mol Biol Rep 27:167–173

    Article  CAS  PubMed  Google Scholar 

  35. Thirunavukkarasu K, Pei Y, Moore TL, Wang H, Yu XP, Geiser AG et al (2006) Regulation of human ADAMTS-4 promoter by transcription factors and cytokines. Biochem Biophys Res Commun 345:197–204

    Article  CAS  PubMed  Google Scholar 

  36. Thirunavukkarasu K, Pei Y, Wei T (2007) Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 34:225–231

    Article  CAS  PubMed  Google Scholar 

  37. Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O et al (2010) Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J Immunol 184:1543–1551

    Article  CAS  PubMed  Google Scholar 

  38. Sandelin A, Carninci P, Lenhard B, Ponjavic J, Hayashizaki Y, Hume DA (2007) Mammalian RNA polymerase II core pro-moters: insights from genome-wide studies. Nat Rev Genet 8:424–436

    Article  CAS  PubMed  Google Scholar 

  39. Wyse BD, Linas SL, Thekkumkara TJ (2000) Functional role of a novel cis-acting element (GAGA box) in human type-1 angiotensin II receptor gene transcription. J Mol Endocrinol 25(1):97–108

    Article  CAS  PubMed  Google Scholar 

  40. Weber JA, Taxman DJ, Lu Q, Gilmour DS (1997) Molecular architecture of the hsp70 promoter after deletion of the TATA box or the upstream regulation region. Mol Cell Biol 17:3799–3808

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Bossone SA, Asselin C, Patel AJ, Marcu KB (1992) MAZ, a zinc finger protein, binds to c-MYC and C2 gene sequences regulating transcriptional initiation and termination. Proc Natl Acad Sci 89:7452–7456

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Jensen ED, Gopalakrishnan R, Westendorf JJ (2010) Regulation of gene expression in osteoblasts. BioFactors 36(1):25–32

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Orimo H (2010) The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch 77(1):4–12

    Article  CAS  PubMed  Google Scholar 

  44. Tawara K, Oxford JT, Jorcyk CL (2011) Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manage Res 3:177–189

    CAS  Google Scholar 

  45. Teitelbaum SL (2000) Bone resorption by osteoclasts. Science 289(5484):1504–1508

    Article  CAS  PubMed  Google Scholar 

  46. Wang WM, Lee S, Steiglitz BM, Scott IC, Lebares CC, Allen ML, Brenner MC, Takahara K, Greenspan DS (2003) Transforming growth factor-beta induces secretion of activated ADAMTS-2. A procollagen III N-proteinase. J Biol Chem 278:19549–19557

    Article  CAS  PubMed  Google Scholar 

  47. Lee S, Solow-Cordero DE, Kessler E, Takahara K, Greenspan DS (1997) Transforming growth factor-beta regulation of bone morphogenetic protein-1/procollagen C-proteinase and related proteins in fibrogenic cells and keratinocytes. J Biol Chem 272:19059–19066

    Article  CAS  PubMed  Google Scholar 

  48. Young J, Kim HM, Seungbok L (2006) Regulation of ADAMTS-2 by 1,25-dihydroxyvitamin D3 in osteoblastic cells. Int J Oral Biol 3(31):93–98

    Google Scholar 

  49. Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14(3):109–119

    Article  CAS  PubMed  Google Scholar 

  50. Pautke C, Schıeker M, Tıscher T (2004) Characterization of osteosarcoma cell lines MG-63, Saos-2 and U-2 OS in comparison to human osteoblasts. Anticancer Res 24(6):3743–3748

    CAS  PubMed  Google Scholar 

  51. Goff BL, Blanchard F, Berthelo JM, Heymann D, Maugar Y (2010) Role for interleukin-6 in structural joint damage and systemic bone loss in rheumatoid arthritis. Jt Bone Spine 77:201–205

    Article  Google Scholar 

Download references

Acknowledgments

Saos-2 (sarcoma osteogenic) was kindly provided by Dr. Kenneth Brown (Cardiff, School of Biosciences, Cardiff UK). MG-63 (human osteosarcoma cell line) cell line was kindly provided by Dr. Deborah Mason.

Funding

This work was supported mainly by the Scientific and Technological Research Council of Turkey (TUBITAK) (212T200) and partially by the Balikesir University Scientific Research Projects Unit (BAP) (2010/39).

Author information

Authors and Affiliations

  1. Department of Biology, Faculty of Science and Literature, Balıkesir University, Balıkesir, 10145, Turkey

    Meltem Alper & Feray Kockar

  2. Department of Biology, Faculty of Science and Letters, Aksaray University, Aksaray, 68100, Turkey

    Meltem Alper

Authors
  1. Meltem Alper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feray Kockar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Feray Kockar.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alper, M., Kockar, F. IL-6 upregulates a disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2) in human osteosarcoma cells mediated by JNK pathway. Mol Cell Biochem 393, 165–175 (2014). https://doi.org/10.1007/s11010-014-2056-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-014-2056-9

Keywords

Search

Navigation