Serum Matrix Metalloproteinase-3 Predicts Radiographic Joint Damage and Functional Disability in Rheumatoid Arthritis

MMP-3 in Rheumatoid Arthritis
Vol. 11 No. 2 : 2016 (209-217)

Sakthiswary R Sakthiswary R
Omimah KJN Omimah KJN
Endom I Endom I
Shaharir SS Shaharir SS
Sridharan R Sridharan R

Abstract
The search for novel biomarkers has taken centre stage in the past decades of research in Rheumatoid Arthritis (RA). The purpose of the present study was to determine the correlation of serum matrix metalloproteinase-3 (MMP-3) with disease activity, joint damage and functional disability in patients with RA. We consecutively recruited RA patients who were under follow-up at the Universiti Kebangsaan Malaysia Medical Centre (UKMMC). Information on the RA disease characteristics were obtained from the medical records and all RA patients were assessed for DAS28 (disease activity score based on 28 joints) and Stanford Health Assessment Questionnaire (HAQ) 8-item Disability Index (HAQ-DI). The hand radiographs of the RA patients were assessed for joint damage using the Modified Sharp Score (MSS).  Serum MMP-3 levels from RA patients and healthy controls were measured using the ELISA method. We recruited a total of 77 RA patients and 18 healthy controls. The serum MMP-3 levels were significantly higher among the RA patients (p<0.05). There were significant correlations between the serum MMP-3 levels and MSS (r =0.327) and HAQ-DI (r=0.256), both p<0.05. The mean serum MMP levels in RA patients with radiographic joint erosions was significantly higher than in patients without erosions (p<0.05). Likewise, the subjects with significant functional impairment i.e HAQ-DI ≥1; had significantly higher mean MMP-3 levels compared to RA patients without significant disability (p<0.05). On multivariate analysis, HAQ-DI remained the independent predictor of serum MMP-3 in RA patients. Serum MMP-3 is a potential biomarker and predictor of radiographic joint damage and functional disability in RA.

Keywords : acquired joint deformity, matrix metalloproteinases, rheumatoid arthritis,

Correspondance Address
Rajalingham Sakthiswary, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia. Tel: +603-91456097 Fax: +603-91456047 E-mail: sakthis5@hotmail.com


References
Aletaha, D., Neogi, T., Silman, A.J., Funovits, J., Felson, D.T., Bingham, C.O., Birnbaum, N.S., Burmester, G.R., Bykerk, V.P., Cohen, M.D., Combe. B., Costenbader, K.H., Dougados, M., Emery, P., Ferraccioli, G., Hazes, J.M., Hobbs, K., Huizinga, T.W., Kavanaugh, A., Kay, J., Kvien, T.K., Laing, T., Mease, P., Ménard, H.A., Moreland, L.W., Naden, R.L., Pincus, T., Smolen, J.S., Stanislawska-Biernat, E., Symmons, D., Tak, P.P., Upchurch, K.S., Vencovsky, J., Wolfe, F., Hawker, G. 2010. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9): 1580-8. Ally, M.M., Hodkinson, B., Meyer, P.W., Musenge, E., Tikly, M., Anderson, R. 2013. Serum matrix metalloproteinase-3 in comparison with acute phase proteins as a marker of disease activity and radiographic damage in early rheumatoid arthritis. Mediators Inflamm 2013: 183653. Arnett, F.C., Edworthy, S.M., Bloch, D.A., Mcshane, D.J., Fries, J.F., Cooper, N.S., Healey, L.A., Kaplan, S.R., Liang, M.H., Luthra, H.S., Medsger, T.A., Mitchell, D.M., Neustadt, D.H., Pinals, R.S., Schaller, J.G., Sharp, J.T., Wilder, R.L., Hunder, G.G. 1988. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3): 315-24. Cheung, N.T., Dawes, P.T., Poulton, K.V., Ollier, W.E., Taylor, D.J., Mattey, D.L. 2000. High serum levels of pro-matrix metalloproteinase-3 are associated with greater radiographic damage and the presence of the shared epitope in patients with rheumatoid arthritis. J Rheumatol 27(4): 882-7. Cunnane, G., Fitzgerald, O., Beeton, C., Cawston, T.E., Bresnihan, B. 2001. Early joint erosions and serum levels of matrix metalloproteinase 1, matrix metalloproteinase 3, and tissue inhibitor of metalloproteinases 1 in rheumatoid arthritis. Arthritis Rheum 44(10): 2263-74. Filippucci, E., Iagnocco, A., Meenagh, G., Riente, L., Delle Sedie, A., Bombardieri, S., Valesini, G., Grassi, W. 2006. Ultrasound imaging for the rheumatologist II. Ultrasonography of the hand and wrist. Clin Exp rheumatol 24(2): 118-122. Fransen, J., van Riel, P.L. 2005. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 23(39): S93-S99. Fries, J.F., Spitz, P., Kraines, R.G., Holman, H.R. 1980. Measurement of patient outcome in arthritis. Arthritis Rheum 23(2): 137-45. Galil, S.M., El-Shafey, A.M., Hagrass, H.A., Fawzy, F., Sammak, A.E. 2016. Baseline serum level of matrix metalloproteinase-3 as a biomarker of progressive joint damage in rheumatoid arthritis patients. Int J Rheum Dis 19(4): 377-84. Galliera, E., Banfi, G., Corsi, M.M. 2010. Human bone disorders: pathological role and diagnostic potential of matrix metalloproteinases. Int J Biochem Cell Biol 42(10): 1590-3. Hueber, A.J., Asquith, D.L., McInnes, I.B., Miller, A.M. 2010. Embracing novel cytokines in RA -complexity grows as does opportunity! Best Pract Res Clin Rheumatol 24(4): 479-87. Ichikawa, Y., Yamada, C., Horiki, T., Hoshina, Y., Uchiyama, M. 1998. Serum matrix metalloproteinase-3 and fibrin degradation product levels correlate with clinical disease activity in rheumatoid arthritis. Clin Exp Rheumatol 16(5): 533-40. Jones, G.C., Riley, G.P., Buttle, D.J. 2008. The role of proteases in pathologies of the synovial joint. Int J Biochem cell biology 40(6-7): 1199-1218. Kobayashi, A., Naito, S., Enomoto, H., Shiomoi, T., Kimura, T., Obata, K., Inoue, K., Okada, Y. 2007. Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med 131(4): 563-70. Mahmoud, R.K., El-Ansary, A.K., El-Eishi, H.H., Kamal, H.M., El-Saeed, N.H. 2005. Matrix metalloproteinases MMP-3 and MMP-1 levels in sera and synovial fluids in patients with rheumatoid arthritis and osteoarthritis. Ital J Biochem 54(3-4): 248-57. McInnes, I.B., Schett, G. 2011. The pathogenesis of rheumatoid arthritis. N Eng J Med 365(23): 2205-19. Okada, Y., Takeuchi, N., Tomita, K., Nakanishi, I., Nagase, H. 1989. Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. Ann Rheum Dis 48(8): 645-53. Pincus, T., Larsen, A., Brooks, R.H., Kaye, J., Nance, E.P., Callahan, L.F. 1997. Comparison of 3 quantitative measures of hand radiographs in patients with rheumatoid arthritis: Steinbrocker stage, Kaye modified Sharp score, and Larsen score. J Rheumatol 24(11): 2106-2112. Prevoo, M.L., van ‘t Hof, M.A., Kuper, H.H., van Leeuwen, M.A., van de Putte, L.B., van Riel, P.L. 1995. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 48: 3844-8. Ribbens, C., Martin y Porras, M., Franchimont, N., Kaiser, M.J., Jaspar, J.M., Damas, P., Houssiau, F.A., Malaise, M.G. 2002. Increased matrix metalloproteinase-3 serum levels in rheumatic diseases: relationship with synovitis and steroid treatment. Ann Rheum Dis 61(4): 161-6. Rohekar, G., Pope, J. 2009. Test-retest reliability of patient global assessment and physician global assessment in rheumatoid arthritis. J Rheumatol 36(10): 2178-82. Rothschild, B.M., Turner, K.R., DeLuca, M.A. 1988. Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama. Science 241(4872): 1498-1501. Shinozaki, M., Inoue, E., Nakajima, A., Hara, M., Tomatsu, T., Kamatani, N., Yamanaka, H. 2007. Elevation of serum matrix metalloproteinase-3 as a predictive marker for the long-term disability of rheumatoid arthritis patients in a prospective observational cohort IORRA. Mod rheumatol 17(5): 403-8. Singer, II., Kawka, D.W., Bayne, E.K., Donatelli, S.A., Weidner, J.R., Williams, H.R., Ayala, J.M., Mumford, R.A., Lark, M.W., Glant, T.T., Nabozny, G.H., David, C.S. 1995. VDIPEN, a metalloproteinase-generated neoepitope, is induced and immunolocalized in articular cartilage during inflammatory arthritis. J Clin Invest 95(5): 2178-86. Urata, Y., Uesato, R., Tanaka, D., Nakamura, Y., Motomura, S. 2012. Treating to target matrix metalloproteinase 3 normalisation together with disease activity score below 2.6 yields better effects than each alone in rheumatoid arthritis patients: T-4 Study. Ann Rheum Dis 71(4): 534-40. Welsing, P.M., van Gestel, A.M., Swinkels, H.L., Kiemeney, L.A., van Riel, P.L. 2001. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum 44(9): 2009-17. Yamanaka, H., Matsuda, Y., Tanaka, M., Sendo, W., Nakajima, H., Taniguchi, A., Kamatani, N. 2000. Serum matrix metalloproteinase 3 as a predictor of the degree of joint destruction during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum 43(4): 852-8. Zucker, S., Lysik, R.M., Zarrabi, M.H., Greenwald, R.A., Gruber, B., Tickle, S.P., Baker, T.S., Docherty, A.J. 1994. Elevated plasma stromelysin levels in arthritis. J Rheumatol 21(12): 2329-33.