1. bookVolume 22 (2014): Issue 4 (December 2014)
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year
access type Open Access

Abnormalities in soluble CD147 / MMPs / TIMPs axis in Ankylosing Spondylitis patients with and without a history of Acute Anterior Uveitis / Anomalii ale axei CD147 solubil / MMPs / TIMPs la pacienții cu spondilită anchilozantă cu sau fără uveită acută anterioară

Published Online: 30 Dec 2014
Page range: 479 - 496
Received: 12 Jun 2014
Accepted: 01 Nov 2014
Journal Details
First Published
08 Aug 2013
Publication timeframe
4 times per year

Ankylosing Spondylitis (AS) is the prototype of the axial form of spondyloarthritis. Despite extensive studies, complex mechanisms related to abnormal cellular and molecular processes in AS are not completely understood. Among proinflammatory mediators such as proinflammatory cytokines, NOS-2, chemokines, which lead to inflammation, matrix metalloproteinases (MMPs) play an important role in inflammatory processes that characterize AS. Therefore, we purposed to evaluate whether the disruption of extracellular MMPs inducer (EMMPRIN/CD147), MMPs and tissue inhibitors of MMPs (TIMPs) homeostasis play a role in the evolution of AS especially in patients with a history of Acute Anterior Uveitis (AAU). For this purpose sera from AS patients and from healthy donors (HDs) were assessed for soluble CD147 (sCD147), MMP-3 and TIMP-1 levels using enzyme-linked immunosorbent assay and for the activity of MMP-2 and -9 gelatinases by gelatin zymography. The experimental results showed that the levels of sCD147, MMP-3 and TIMP-1 were significantly increased in AS patients compared to HDs. sCD147 as well as the ratio MMP-2/sCD147 differentiated AS patients with a history of AAU from those without it. The ratios MMP-2/sCD147, MMP-3/sCD147 and MMP-3/TIMP-1 suggested an imbalance between MMPs and their regulators in AS patients. These results suggest that MMPs/sCD147 ratios could be potential biomarkers to strengthen the characterization of AS patients and to predict disease evolution. Positive or negative correlations between some of the experimental and/or clinical features of AS patients and the therapy also highlight the usefulness of the evaluation of these biomarkers to identify an individualized and efficient therapy.


Cuvinte cheie

1. Slobodin G, Rosner I, Rimar D, Boulman N, Rozenbaum M, Odeh M. Ankylosing spondylitis: field in progress. Isr Med Assoc J. 2012;14(12):763-7.Search in Google Scholar

2. Thomas GP, Brown MA. Genetics and genomics of ankylosing spondylitis. Immunol Rev. 2010;233(1):162-80. DOI: 10.1111/j.0105-2896.2009.00852.x10.1111/j.0105-2896.2009.00852.x20192999Search in Google Scholar

3. Snelgrove T, Lim S, Greenwood C, Peddle L, Hamilton S, Inman R, et al. Association of toll-like receptor 4 variants and ankylosing spondylitis: a case-control study. J Rheumatol. 2007;34(2):368-70.Search in Google Scholar

4. De Vlam K. Soluble and tissue biomarkers in ankylosing spondylitis. Best Pract Res Clin Rheumatol. 2010;24(5):671-82. DOI: 10.1016/j.berh.2010.05.00910.1016/j.berh.2010.05.00921035087Search in Google Scholar

5. Wang QH, Zhang SZ, Xue J, Wu HX. Serum metalloproteinase-3 levels in assessing efficacy of Etanercept in patients with ankylosing spondylitis. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2010;39(4):409-14 (abstract).Search in Google Scholar

6. Maksymowych WP, Landewé R, Conner-Spady B, Dougados M, Mielants H, van der Tempel H, Poole AR, Wang N, van der Heijde D. Serum matrix metalloproteinase 3 is an independent predictor of structural damage progression in patients with ankylosing spondylitis.Search in Google Scholar

Arthritis Rheum. 2007;56(6):1846-53 DOI: 10.1002/ art.22589Search in Google Scholar

7. Gouveia EB, Elmann D, Morales MS. Ankylosing spondylitis and uveitis: overview. Rev Bras Reumatol. 2012;52(5):742-56.Search in Google Scholar

8. El Maghraoui A. Extra-articular manifestations of ankylosing spondylitis: prevalence, characteristics and therapeutic implications. Eur J Intern Med. 2011;22(6):554-60. DOI: 10.1016/j.ejim.2011.06.00610.1016/j.ejim.2011.06.00622075279Search in Google Scholar

9. Robertson LP, Davis MJ. A longitudinal study of disease activity and functional status in a hospital cohort of patients with ankylosing spondylitis. Rheumatology (Oxford). 2004;43(12):1565-8. DOI: 10.1093/rheumatology/ keh386Search in Google Scholar

10. Chang JH, McCluskey PJ, Wakefield D. 2009. Acute Anterior Uveitis and HLA-B27: What’s New? in Uveitis and Immunological Disorders Progress III, U Pleyer, JV Forrester eds. Springer-Verlag, Berlin Heidelberg. p. 9-18. DOI: 10.1007/978-3-540-69459-5_210.1007/978-3-540-69459-5_2Search in Google Scholar

11. Li H, Yoneda M, Takeyama M, Sugita I, Tsunekawa H, Yamada H, et al. Effect of infliximab on tumor necrosis factor-alpha-induced alterations in retinal microvascular endothelial cells and retinal pigment epithelial cells. J Ocul Pharmacol Ther. 2010;26(6):549-56. DOI: 10.1089/jop.2010.007910.1089/jop.2010.007921054185Search in Google Scholar

12. Di Girolamo N, Verma MJ, McCluskey PJ, Lloyd A, Wakefield D. Increased matrix metalloproteinases in the aqueous humor of patients and experimental animals with uveitis. Curr Eye Res. 1996;15(10):1060-8.10.3109/027136896090176568921246Search in Google Scholar

DOI: 10.3109/0271368960901765610.3109/02713689609017656Search in Google Scholar

13. Cuello C, Wakefield D, Di Girolamo N. Neutrophil accumulation correlates with type IV collagenase/gelatinase activity in endotoxin induced uveitis. Br J Ophtalmol. 2002;86(3):290-5. DOI: 10.1136/bjo.86.3.29010.1136/bjo.86.3.290177105911864886Search in Google Scholar

14. Yamada H, Yoneda M, Inaguma S, Watanabe D, Banno S, Yoshikawa K, et al. Infliximab counteracts tumor necrosis factor-α-enhanced induction of matrix metalloproteinases that degrade claudin and occludin in non-pigmented ciliary epithelium. Biochem Pharmacol. 2013;85(12):1770-82. DOI: 10.1016/j.bcp.2013.04.00610.1016/j.bcp.2013.04.00623603294Search in Google Scholar

15. Martin TM, Bye L, Modi N, Stanford MR, Vaughan R, Smith JR, et al. Genotype analysis of polymorphisms in autoimmune susceptibility genes, CTLA-4 and PTPN22, in an acute anterior uveitis cohort. Mol Vis. 2009;15:208-12.Search in Google Scholar

16. Fossum S, Mallett S, Barclay AN. The MRC OX-47 antigen is a member of the immunoglobulin superfamily with an unusual transmembrane sequence. Eur J Immunol. 1991;21(3):671-9. DOI: 10.1002/eji.183021032010.1002/eji.18302103202009910Search in Google Scholar

17. Koch C, Staffler G, Hüttinger R, Hilgert I, Prager E, Cerný J, et al. T cell activation-associated epitopes of CD147 in regulation of the T cell response, and their definition by antibody affinity and antigen density.Search in Google Scholar

Int Immunol. 1999;11(5):777-86. DOI: 10.1093/intimm/Search in Google Scholar

11.5.777Search in Google Scholar

18. Määttä M, Tervahartiala T, Kaarniranta K, Tang Y, Yan L, Tuukkanen J, et al. Immunolocalization of EMMPRIN (CD147) in the human eye and detection of soluble form of EMMPRIN in ocular fluids. Curr Eye Res. 2006;31(11):917-24. DOI: 10.1080/0271368060093229010.1080/02713680600932290Search in Google Scholar

19. Biswas C. Tumor cell stimulation of collagenase production by fibroblasts. Biochem Biophys Res Commun. 1982;109(3):1026-34. DOI: 10.1016/0006-291X(82)92042-310.1016/0006-291X(82)92042-3Search in Google Scholar

20. Philp NJ, Ochrietor JD, Rudoy C, Muramatsu T, Linser PJ. Loss of MCT1, MCT3, and MCT4 expression in the retinal pigment epithelium and neural retina of the 5A11/basigin-null mouse. Invest Ophthalmol Vis Sci. 2003;44(3):1305-11. DOI: 10.1167/iovs.02-055210.1167/iovs.02-055212601063Search in Google Scholar

21. Gabison EE, Mourah S, Steinfels E, Yan L, Hoang-Xuan T, Watsky MA, et al. Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction.Search in Google Scholar

Am J Pathol. 2005;166(1):209-19. DOI: 10.1016/ S0002-9440(10)62245-6Search in Google Scholar

22. Iacono KT, Brown AL, Greene MI, Saouaf SJ. CD147 immunoglobulin superfamily receptor function and role in pathology. Exp Mol Pathol. 2007;83(3):283-95.10.1016/j.yexmp.2007.08.014221173917945211Search in Google Scholar

DOI: 10.1016/j.yexmp.2007.08.01410.1016/j.yexmp.2007.08.014Search in Google Scholar

23. Taylor PM, Woodfield RJ, Hodgkin MN, Pettitt TR, Martin A, Kerr DJ, et al. Breast cancer cell-derived EMMPRIN stimulates fibroblast MMP2 release through a phospholipase A(2) and 5-lipoxygenase catalyzed pathway.Search in Google Scholar

Oncogene. 2002;21(37):5765-72. DOI: 10.1038/ sj.onc.120570210.1038/sj.onc.120570212173047Search in Google Scholar

24. Sidhu SS, Mengistab AT, Tauscher AN, LaVail J, Basbaum C. The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactions. Oncogene. 2004;23(4):956-63. DOI: 10.1038/sj.onc.120707010.1038/sj.onc.120707014749763Search in Google Scholar

25. Egawa N, Koshikawa N, Tomari T, Nabeshima K, Isobe T, Seiki M. Membrane type 1 matrix metalloproteinase (MT1-MMP/MMP-14) cleaves and releases a 22-kDa extracellular matrix metalloproteinase inducer (EMMPRIN) fragment from tumor cells. J Biol Chem. 2006;281(49):37576-85. DOI: 10.1074/jbc.10.1074/jbcSearch in Google Scholar

M606993200Search in Google Scholar

26. Onodera J, Onodera S, Kondo E, Betsuyaku T, Yasuda K. A soluble factor (EMMPRIN) in exudate influences knee motion after total arthroplasty. Knee Surg Sports Traumatol Arthrosc. 2009;17(3):298-304. DOI: 10.1007/s00167-008-0688-610.1007/s00167-008-0688-619089410Search in Google Scholar

27. Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Hamaguchi Y, et al. Increased serum soluble CD147 levels in patients with systemic sclerosis: association with scleroderma renal crisis. Clin Rheumatol. 2012;31(5):835-9. DOI: 10.1007/s10067-012-1949-910.1007/s10067-012-1949-922298186Search in Google Scholar

28. Wang M, Huang ZX, Pan YF, Zhang FC, Zheng BR, Deng WM, et al. Expressions of CD147 in peripheral monocytes and T lymphocytes of patients with ankylosing spondylitis. Zhonghua Yi Xue Za Zhi. 2010;90(41):2902-6 (abstract).Search in Google Scholar

29. Dhir V, Srivastava R, Aggarwal A. Circulating Levels of Soluble Receptor Activator of NF- κ B Ligand and Matrix Metalloproteinase 3 (and Their Antagonists) in Asian Indian Patients with Ankylosing Spondylitis.Search in Google Scholar

Int J Rheumatol. 2013;2013:814350. DOI: 10.1155/2013/81435010.1155/2013/814350Search in Google Scholar

30. Veidal SS, Larsen DV, Chen X, Sun S, Zheng Q, Bay-Jensen AC, et al. MMP mediated type V collagen degradation (C5M) is elevated in ankylosing spondylitis.Search in Google Scholar

Clin Biochem. 2012;45(7-8):541-6 DOI: 10.1016/j. clinbiochem.2012.02.007Search in Google Scholar

31. Mattey DL, Packham JC, Nixon NB, Coates L, Creamer P, Hailwood S, et al. Association of cytokine and matrix metalloproteinase profiles with disease activity and function in ankylosing spondylitis. Arthritis Res Ther. 2012;14(3):R127 DOI: 10.1186/ar385710.1186/ar3857Search in Google Scholar

32. Moll JM, Wright V. New York clinical criteria for ankylosing spondylitis. A statistical evaluation. Ann Rheum Dis. 1973;32(4):354-63. DOI: 10.1136/ard.32.4.35410.1136/ard.32.4.354Search in Google Scholar

33. Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis.Search in Google Scholar

A proposal for modification of the New York criteria.Search in Google Scholar

Arthritis Rheum. 1984;27(4):361-8. DOI: 10.1002/ art.178027040110.1002/art.1780270401Search in Google Scholar

34. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol. 1994;21(12):2286-91.Search in Google Scholar

35. Lukas C, Landewé R, Sieper J, Dougados M, Davis J, Braun J, et al. Assessment of SpondyloArthritis international Society. Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(1):18-24.10.1136/ard.2008.094870Search in Google Scholar

DOI: 10.1136/ard.2008.09487010.1136/ard.2008.094870Search in Google Scholar

36. Calin A, Garrett S, Whitelock H, Kennedy LG, O’Hea J, Mallorie P, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol. 1994;21(12):2281-5.Search in Google Scholar

37. Matache C, Stefanescu M, Dragomir C, Tanaseanu S, Onu A, Ofiteru A, et al. Matrix metalloproteinase-9 and its natural inhibitor TIMP-1 expressed or secreted by peripheral blood mononuclear cells from patients with systemic lupus erythematosus. J Autoimmun. 2003; 20(4): 323-31. DOI: 10.1016/S0896-8411(03)00037-410.1016/S0896-8411(03)00037-4Search in Google Scholar

38. Chen CH, Lin KC, Chen HA, Liao HT, Liang TH, Wang HP, et al. Association of acute anterior uveitis with disease activity, functional ability and physical mobility in patients with ankylosing spondylitis: a cross-sectional study of Chinese patients in Taiwan. Clin Rheumatol. 2007;26(6):953-7. DOI: 10.1007/s10067-006-0403-210.1007/s10067-006-0403-217021671Search in Google Scholar

39. Berg IJ, Semb AG, van der Heijde D, Kvien TK, Hisdal J, Olsen IC, et al. Uveitis is associated to hypertension and atherosclerosis in patients with ankylosing spondylitis: a cross-sectional study. Semin Arthritis Rheum.Search in Google Scholar

2014. pii: S0049-0172(14)00111-5. doi: 10.1016/j. semarthrit.2014.05.017. DOI: 10.1016/j.semarthrit.Search in Google Scholar

2014.05.017Search in Google Scholar

40. Cordiali-Fei P, Trento E, D’Agosto G, Bordignon V, Mussi A, Ardigó M, et al. Effective therapy with anti- TNF-alpha in patients with psoriatic arthritis is associated with decreased levels of metalloproteinases and angiogenic cytokines in the sera and skin lesions.Search in Google Scholar

Ann N Y Acad Sci. 2007;1110:578-89. DOI: 10.1196/ annals.1423.062Search in Google Scholar

41. Chen CH, Lin KC, Yu DT, Yang C, Huang F, Chen HA, et al. Serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in ankylosing spondylitis: MMP-3 is a reproducibly sensitive and specific biomarker of disease activity. Rheumatology (Oxford). 2006;45(4):414-20. DOI: 10.1093/rheumatology/kei20810.1093/rheumatology/kei20816287916Search in Google Scholar

42. Yurchenko V, Constant S, Eisenmesser E, Bukrinsky M. Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics. Clin Exp Immunol. 2010;160(3):305-17. DOI: 10.1111/j.1365-2249.2010.04115.x10.1111/j.1365-2249.2010.04115.x288310020345978Search in Google Scholar

43. Pistol G, Matache C, Calugaru A, Stavaru C, Tanaseanu S, Ionescu R, et al. Roles of CD147 on T lymphocytes activation and MMP-9 secretion in systemic lupus erythematosus.Search in Google Scholar

J Cell Mol Med. 2007;11(2):339-48. DOI: 10.1111/j.1582-4934.2007.00022.x10.1111/j.1582-4934.2007.00022.x382283217488482Search in Google Scholar

44. Han YP, Tuan TL, Wu H, Hughes M, Garner WL.Search in Google Scholar

TNF-alpha stimulates activation of pro-MMP2 in human skin through NF-(kappa)B mediated induction of MT1-MMP. J Cell Sci. 2001;114(Pt 1):131-139.10.1242/jcs.114.1.131243508911112697Search in Google Scholar

45. Bellayr IH, Mu X, Li Y. Biochemical insights into the role of matrix metalloproteinases in regeneration: challenges and recent developments. Future Med Chem. 2009;1(6):1095-111. DOI: 10.4155/fmc.09.8310.4155/fmc.09.83279413820161478Search in Google Scholar

46. Kaneider NC, Mosheimer B, Günther A, Feistritzer C, Wiedermann CJ. Enhancement of fibrinogen-triggered pro-coagulant activation of monocytes in vitro by matrix metalloproteinase-9. Thromb J. 2010;8(1):2-7.10.1186/1477-9560-8-2283762020181055Search in Google Scholar

DOI: 10.1186/1477-9560-8-210.1186/1477-9560-8-2Search in Google Scholar

47. Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, et al. A four-marker signature of TNFRII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma. J Transl Med. 2014,12:19. DOI: 10.1186/1479-5876-12-1910.1186/1479-5876-12-19390938424457057Search in Google Scholar

48. Gehlen M, Regis KC, Skare TL. Demographic, clinical, laboratory and treatment characteristics of spondyloarthritis patients with and without acute anterior uveitis.Search in Google Scholar

Sao Paolo Med J. 2012;130(3):141-4. DOI: 10.1590/ S1516-31802012000300002 10.1590/S1516-31802012000300002Search in Google Scholar

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