Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 5, May, p. 665–670

doi: 10.17219/acem/94065

Publication type: original article

Language: English

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Matrix metalloproteinase-3 levels in relation to disease activity and radiological progression in rheumatoid arthritis

Turkan Tuncer1,A,B,C, Arzu Kaya1,A,B,C, Arif Gulkesen1,A,B, Gul Ayden Kal2,B, Dilara Kaman3,C, Gurkan Akgol1,A,B,D

1 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Fırat University, Elazığ, Turkey

2 Department of Physical Medicine and Rehabilitation, Elazığ Training and Research Hospital, Turkey

3 Department of Biochemistry and Clinical Biochemistry School of Medicine, Fırat University, Elazığ, Turkey


Background. Rheumatoid arthritis (RA) is a chronic inflammatory and systemic disease of unknown etiology that primarily affects synovial joints and involves progressive destruction around the joints. Inflammation starting in the joint synovium causes the destruction of cartilage, bone and other adjacent tissues with pannus formation.
Objectives. The aim of this study was to evaluate serum matrix metalloproteinase-3 (MMP-3) levels and their clinical and radiological significance in patients with rheumatoid arthritis.
Material and Methods. The study included 59 patients with RA and 30 healthy controls. Serum MMP-3 levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. Patients with a Disease Activity Score 28 (DAS28) ≤3.2 were categorized as having lower disease activity, while a DAS28 score >3.2 indicated patients with moderate/high disease activity. Additionally, the patients were divided into 2 groups in terms of disease duration: early RA (disease duration ≤2 years) and established RA (disease duration ≥2 years). Functional disability was evaluated using the Health Assessment Questionnaire (HAQ) and Nottingham Health Profile (NHP). Radiographs were scored using modified Larsen scoring.
Results. Serum MMP-3 levels in patients with RA were significantly higher than in controls (p = 0.001). Serum MMP-3 levels were correlated with laboratory and clinical parameters of disease activity, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), DAS28, and HAQ score; the exceptions were rheumatoid factor (RF) and cyclic citrullinated peptides (CCP). The serum MMP-3 levels of RA patients with moderate/high disease activity were found to be significantly higher than those of the patients with low disease activity (p < 0.001). However, MMP-3 levels were found to be similar in both established and early RA patients (p = 0.927). Additionally, the modified Larsen scores, which indicate structural damage, correlated significantly with serum MMP-3 levels (p = 0.001).
Conclusion. These results indicate that serum MMP-3 levels may be used as an indicator for structural damage such as erosions in the early stages of the disease, and to monitor disease activity.

Key words

rheumatoid arthritis, matrix metalloproteinase 3, disease activity, modified Larsen score

References (47)

  1. Ergin S. Romatoid Artrit ve Sjögren Sendromu. In: Beyazova M, Gökçe-Kutsal Y, eds. Fiziksel Tıp ve Rehabilitasyon, vol. 2. Ankara, Turkey: Güneş Kitabevi; 2000:1549–1576.
  2. Koniçe M, Eryavuz M. Romatoid Artrit. In: Tüzün F. Eryavuz M. Akarırmak Ü, eds. Hareket Sistemi Hastalıkları. İstanbul, Turkey: Nobel Tıp Kitabevi; 1997:85–98.
  3. Mevorach D, Paget SA. Rheumatoid Arthritis. In: Paget SA, Gibofsky A, Beary JF, eds. Manual of Rheumatology and Outpatient Orthopedic Disorders. 4th ed, Lippincott Williams & Wilkins; 2000:192–229.
  4. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73(3):492–509.
  5. Lillegraven S, Prince FH, Shadick NA, et al. Remission and radiographic outcome in rheumatoid arthritis: Application of the 2011 ACR/EULAR remis-sion criteria in an observational cohort. Ann Rheum Dis. 2012;71(5):681–686.
  6. Aletaha D, Smolen JS. Joint damage in rheumatoid arthritis progresses in remission according to the Disease Activity Score in 28 joints and is driven by residual swollen joints. Arthritis Rheum. 2011;63(12):3702–3711.
  7. Hambardzumyan K, Bolce R, Saevarsdottir S, et al. Pretreatment multi-biomarker disease activity score and radiographic progression in early RA: Results from the SWEFOT trial. Ann Rheum Dis. 2015;74(6):1102–1109.
  8. Markusse IM, Dirven L, van den Broek M, et al. A multibiomarker disease activity score for rheumatoid arthritis predicts radiographic joint damage in the BeSt study. J Rheumatol. 2014;41(11):2114–2119.
  9. Vise R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: Structure, function, and biochemistry. Circ Res. 2003;92(8):827–839.
  10. Denarie D, Constant E, Thomas T, Marotte H. Could biomarkers of bone, cartilage or synovium turnover be used for relapse prediction in rheumatoid arthritis patients? Mediators Inflamm. 2014;2:537324.
  11. Ma JD, Zhou JJ, Zheng DH, et al. Serum matrix metalloproteinase-3 as a noninvasive biomarker of histological synovitis for diagnosis of rheumatoid arthritis. Mediators Inflamm. 2014;2014:179–284.
  12. Ma JD, Ou-Yang X, Zheng DH, et al. Combined detection of serum matrix metalloproteinase-3 and C-reactive protein in disease activity meas-urement in female patients with rheumatoid arthritis. Chin J Clinicians (Electronic Edition). 2013;8:3301–3305.
  13. Arnett FC, Edworthy SM, Bloch DA, et al. American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31(3):315–324.
  14. Prevoo MLL, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LBA, van Riel PL. Modified disease activity scores that include twen-ty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44–48.
  15. Fransen J, Stucki G, van Riel PL. Rheumatoid arthritis measures: Disease Activity Score (DAS), Disease Activity Score-28 (DAS28), Rapid Assessment of Disease Activity in Rheumatology (RADAR), and Rheumatoid Arthritis Disease Activity Index (RADAI). Arthritis Rheum. 2003;49(9):214–224.
  16. Kucukdeveci AA, Sahin H, Ataman S, Griffths B, Tennant A. Issues in cross-cultural validity: Example from the adaptation reliability and validity testing of a Turkish version of the Stanford Health Assessment Questionnaire (HAQ). Arthritis Care Res. 2004;51(1):14–19.
  17. Larsen A. How to apply Larsen score in evaluating radiographs of rheumatoid arthritis in long-term studies. J Rheumatol. 1995;22(10):1974–1975.
  18. Mota LM, Cruz BA, Brenol CV, et al; Brazilian Society of Rheumatology. 2011 Consensus of the Brazilian Society of Rheumatology for diagnosis and early assessment of rheumatoid arthritis. Rev Bras Reumatol. 2011;51(3):199–219.
  19. Porto LS, Tavares Júnior WC, Costa DA, Lanna CC, Kakehasi AM. Anti-CCP antibodies are not a marker of severity in established rheumatoid arthritis: A magnetic resonance imaging study. Rev Bras Reumatol. 2017;57(1):15–22.
  20. Kroot EJ, de Jong BA, van Leeuwen MA, et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2000;43(8):1831–1835.
  21. Vencovsky J, Machacek S, Sedova L, et al. Autoantibodies can be prognostic markers of an erosive disease in early rheumatoid arthritis. Ann Rheum Dis. 2003;62(5):427–430.
  22. Forslind K, Ahlmén M, Eberhardt K, Hafström I, Svensson B; BARFOT Study Group. Prediction of radiological outcome in early rheumatoid arthritis in clinical practice: Role of antibodies to citrullinated peptides (anti-CCP). Ann Rheum Dis. 2004;63(9):1090–1095.
  23. Quinn MA, Gough AK, Green MJ, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford). 2006;45(4):478–480.
  24. Nell VP, Machold KP, Stamm TA, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis. 2005;64(12):1731–1736.
  25. del Val del Amo N, Ibanez Bosch R, Fito Manteca C, Gutierrez Polo R, Loza Cortina E. Anti-cyclic citrullinated peptide antibody in rheumatoid arthritis: Relation with disease aggressiveness. Clin Exp Rheumatol. 2006;24(3):281–286.
  26. Alexiou I, Germenis A, Ziogas A, Theodoridou K, Sakkas LI. Diagnostic value of anti-cyclic citrullinated peptide antibodies in Greek patients with rheumatoid arthritis. BMC Musculoskelet Dis. 2007;8:37.
  27. Syversen SW, Gaarder PI, Goll GL, et al. High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: Results from a 10-year longitudinal study. Ann Rheum Dis. 2008;67(2):212–217.
  28. Kumagai S, Nishimura K, Hayashi N, Topics on immunological tests for rheumatoid arthritis [in Japanese]. Rinsho Byori. 2004;52(10):836–843.
  29. Hayashi N, Kumagai S. New diagnostic tests for rheumatoid arthritis [in Japanese]. Rinsho Byori. 2003;51(10):1030–1035.
  30. Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516.
  31. Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds. Rheumatology. 3rd ed. New York, NY: Mosby; 2003:753–937.
  32. Taylor DJ, Cheung NT, Dawes PT. Increased serum pro MMP-3 in inflammatory arthritides: A potential indicator of synovial inflammatory monokine activity. Ann Rheum Dis. 1994;53(11):768–772.
  33. Kobayashi A, Naito S, Enomoto H, et al. Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med. 2007;131(4):563–570.
  34. Klimiuk PA, Sierakowski S, Domyslawska I, Chwiecko J. Effect of repeated infliximab therapy on serum matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with rheumatoid arthritis. J Rheumatol. 2004;31(2):28–42.
  35. Houseman M, Potter C, Marshall N, et al. Baseline serum MMP-3 levels in patients with rheumatoid arthritis are still independently predictive of radiographic progression in a longitudinal observational cohort at 8 years follow up. Arthritis Res Ther. 2012;14(1):30.
  36. Shinozaki M, Inoue E, Nakajima A, et al. 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. 2007;17(5):403–408.
  37. Young-Min S, Cawston T, Marshall N, et al. Biomarkers predict radiographic progression in early rheumatoid arthritis and perform well compared with traditional markers. Arthritis Rheum. 2007;56(10):3236–3247.
  38. Bingham S, Emery P. Resistant rheumatoid arthritis clinics: A necessary development? Rheumatology (Oxford). 2000;39(1):2–5.
  39. Balsa A, Carmona L, Gonzalez-Alvaro I, Belmonte MA, Tena X, Sanmarti R; EMECAR Study Group. Value of Disease Activity Score 28 (DAS28) and DAS28-3 compared to American College of Rheumatology-defined remission in rheumatoid arthritis. J Rheumatol. 2004;31(1):40–46.
  40. Green MJ, Gough AKS, Devlin J, et al. Serum MMP-3 and MMP-1 and progression of joint damage in early rheumatoid arthritis. Rheumotology (Oxford). 2003;42(1):83–88.
  41. Tchetverikov I, Lard LR, DeGroot J, et al. Matrix metalloproteinases-3, -8, -9 as markers of disease activity and joint damage progression in early rheumatoid arthritis. Ann Rheum Dis. 2003;62:1094–1099.
  42. Posthumus MD, Limburg PC, Westra J, et al. Serum levels of matrix metalloproteinase-3 in relation to the development of radiological damage in patients with rheumatoid arthritis. Rheumatology (Oxford). 1999;38(11):1081–1087.
  43. Yamanaka H, Matsuda Y, Tanaka M, et al. Serum matrix metalloproteinase 3 as a predıctor of the degree of joint destructıon during the six months after measurement, in patients with early rheumatoid arthritis. Arthritis Rheum. 2000;43(4):852–858.
  44. Posthumus MD, Limburg PC, Westra J, Leeuwen MA. Ruswijck MH. Serum matrix metalloproteinase 3 levels during treatment with sulfasalazine or combination of methotrexate and sulfasalazine in patients with early rheumatoid arthritis. J Rheumatol. 2002;29(5):883–889.
  45. Niki Y, Takeuchi T, Nakayama M, et al. Clinical significance of cartilage biomarkers for monitoring structural joint damage in rheumatoid arthritis patients treated with anti-TNF therapy. PLoS One. 2012;7(5):e37447.
  46. Mamehara A, Sugimoto T, Sugiyama D, et al. Serum matrix metalloproteinase-3 as predictor of joint destruction in rheumatoid arthritis, treated with non-biological disease modifying anti-rheumatic drugs. Kobe J Med Sci. 2010;56(3):98–107.
  47. Kobayashi A, Naito S, Enomoto H, et al. Serum levels of matrix metalloproteinase 3 (stromelysin 1) for monitoring synovitis in rheumatoid arthritis. Arch Pathol Lab Med. 2007;131:563–570.