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Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease activity and radiographic progression

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Abstract

This study aims to investigate the serum levels of cysteine proteases cathepsins B and H and their inhibitors stefin A, stefin B, and cystatin C, as well as traditional inflammatory markers such as C-reactive protein in patients with rheumatoid arthritis and to correlate these markers with scores of disease activity and radiographic progression. Seventy-two patients with rheumatoid arthritis were included from two previously described cohorts of patients with chronic polyarthritis. At inclusion, disease activity was assessed by a 28-joint count, patient global assessment, and serum C-reactive protein. Erosive status of hands and wrists was expressed by the Larsen score and recorded at inclusion and after 1 year. Serum levels of cathepsin B, cathepsin H, stefin A, stefin B, and cystatin C were determined by enzyme-linked immunosorbent assay. Neither cathepsin B nor cathepsin H serum levels were associated with disease activity, presence or progression of erosive disease. Number of swollen joints correlated with serum levels of stefin A and B and correlated negatively with cystatin C serum levels. Erosive disease was associated with high serum levels of C-reactive protein and stefin A and low serum levels of cystatin C. Progression of radiographic destruction was associated with high serum levels of C-reactive protein, stefin A and B, whereas serum levels of cystatin C were not associated with radiographic progression. The findings in this study support further investigation in the regulation of the activity of cathepsins and their inhibitors in erosive rheumatoid arthritis.

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References

  1. Cunnane G, Fitzgerald O, Hummel KM, Gay RE, Gay S et al (1999) Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis. Rheumatology 38:34–42

    Article  PubMed  CAS  Google Scholar 

  2. Cunnane G, Fitzgerald O, Hummel KM, Youssef PP, Gay RE et al (2001) Synovial tissue protease gene expression and joint erosions in early rheumatoid arthritis. Arthritis Rheum 44:1744–1753

    Article  PubMed  CAS  Google Scholar 

  3. Hansen T, Petrow PK, Gaumann A, Keyzer GM, Eysel P et al (2000) Cathepsin B and its endogenous inhibitor cystatin C in rheumatoid arthritis synovium. J Rheumatol 27(4):859–865

    PubMed  CAS  Google Scholar 

  4. Trabant A, Gay RE, Fassbender HG, Gay S (1991) Cathepsin B in synovial cells at the site of joint destruction in rheumatoid arthritis. Arthritis Rheum 34:1444–1451

    Article  Google Scholar 

  5. Solau-Gervais E, Zerimech F, Lemaire R, Fontaine C, Huet G, Flipo RM (2007) Cysteine and serine proteases of synovial tissue in rheumatoid arthritis and osteoarthritis. Scand J Rheumatol 36:373–737

    Article  PubMed  CAS  Google Scholar 

  6. Keyszer G, Lambiri I, Keysser M, Keysser C, Nagel R et al (1998) Matrix metalloproteinases, but not cathepsins B, H, and L or their inhibitors in peripheral blood of patients with rheumatoid arthritis are potentially useful markers of disease activity. Z Rheumatol 57:392–398

    Article  PubMed  CAS  Google Scholar 

  7. Biroc SL, Gay S, Hummel K, Magill C, Palmer JT et al (2001) Cysteine protease activity is up-regulated in inflamed ankle joints of rats with adjuvant-induced arthritis and decreases with in vivo administration of a vinyl sulfone cysteine protease inhibitor. Arthritis Rheum 44:703–711

    Article  PubMed  CAS  Google Scholar 

  8. Keyszer G, Redlich A, Haupl T, Zacher J, Sparmann M et al (1998) Differential expression of cathepsins B and L compared with matrix metalloproteinases and their respective inhibitors in rheumatoid arthritis and osteoarthritis. Arthritis Rheum 41:1378–1387

    Article  PubMed  CAS  Google Scholar 

  9. Kos J, Lah TT (1998) Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer. Oncol Rep 5:1349–1361

    PubMed  CAS  Google Scholar 

  10. Finckh A, Simard JF, Duryea J, Liang MH, Huang J, Daneel S, Forster A, Gabay C, Guerne PA (2006) The effectiveness of anti-tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: a population-based study. Arthritis Rheum 54:54–59

    Article  PubMed  CAS  Google Scholar 

  11. Arnett FC, Edworthy SM, Bloch DA et al (1988) The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  PubMed  CAS  Google Scholar 

  12. Hansen M, Florescu A, Stoltenberg M, Pødenphant J, Pedersen-Zbinden B, Hørslev-Petersen K, Hyldstrup L, Lorenzen I (1996) Bone loss in rheumatoid arthritis. Influence of disease activity, duration of the disease, functional capacity, and corticosteroid treatment. Scand J Rheumatol 25:367–376

    Article  PubMed  CAS  Google Scholar 

  13. Jacobsen S, Madsen HO, Klarlund M, Jensen T, Skjødt H, Jensen KE, Svejgaard A, Garred P, TIRA Group (2001) The influence of mannose binding lectin polymorphisms on disease outcome in early polyarthritis. J Rheumatol 28:935–942

    PubMed  CAS  Google Scholar 

  14. Larsen A, Dale K, Eek M (1977) Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn (Stockh) 18:481–491

    CAS  Google Scholar 

  15. Kos J, Stabuc B, Schweiger A, Krasovec M, Cimerman N, Kopitar-Jerala N, Vrhovec I, Cathepsin V (1997) H and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. Clin Cancer Res 3:1815–1822

    PubMed  CAS  Google Scholar 

  16. Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brϋnner N (2000) Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis. Clin Cancer Res 6:505–511

    PubMed  CAS  Google Scholar 

  17. Solau-Gervaise ZF, Lemaire R, Fontaine C, Huet G, Flipo RM (2007) Cysteine and serine proteases of synovial tissue in rheumatoid arthritis and osteoarthritis. Scand J Rheumatol 36:373–377

    Article  Google Scholar 

  18. Hashimoto Y, Kakegawa H, Narita Y, Hachiya Y, Hayakawa T, Kos J, Turk V, Katunuma N (2001) Medical significance of specific accumulation of cathepsin B in synovial fluid of patients with rheumatoid arthritis. Biol Chem Res Commun 283:334–339

    Article  CAS  Google Scholar 

  19. Skoumal M, Haberhauer G, Kolarz G, Hawa G, Woloszczuk W et al (2005) Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction. Arthritis Res Ther 7:R65–R70

    Article  PubMed  CAS  Google Scholar 

  20. Bokarewa M, Abrahamson M, Levshin N, Egesten A, Grubb A, Dahlberg L, Tarkowski A (2007) Cystatin C binds serum amyloid A, downregulating its cytokine-generating properties. J Rheumatol 34:1293–1301

    PubMed  CAS  Google Scholar 

  21. Gunatilleke SS, de Oliveira CA, McCammon JA, Barrios AM (2008) Inhbition of cathepsin B by Au(I) complexes: a kinetic and computational study. J Biol Inorg Chem 13:555–561

    Article  PubMed  CAS  Google Scholar 

  22. Abisi S, Burnand KG, Humphries J, Waltham M, Taylor P, Smith A (2008) Effect of statins on proteolytic activity in the wall of abdominal aortic aneurysms. Br J Surg 95:333–337

    Article  PubMed  CAS  Google Scholar 

  23. Esser RE, Watts LM, Angelo RA, Thornburg LP, Prior JJ et al (1993) The effects of fluoromethyl ketone inhibitors of cathepsin B on adjuvant induced arthritis. J Rheumatol 207:1176–1183

    Google Scholar 

  24. Svelander L, Erlandsson-Harris H, Astner L, Grabowska U, Klareskog L, Lindstrom E, Hewitt E (2009) Inhibition of cathepsin K reduces bone erosion, cartilage degradation and inflammation evoked by collagen-induced arthritis in mice. Eur J Pharmacol 24:155–162

    Article  Google Scholar 

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Correspondence to Søren Jacobsen.

Additional information

Members of the DRD study group in alphabetical order: Adrian Florescu, Michael S. Hansen, Kim Hørslev-Petersen, Jan Pødenphant, and Michael Stoltenberg. Members of the TIRA study group in alphabetical order: Michael S. Hansen, Merete Lund Hetland, Søren Jacobsen, Trine W. Jensen, Julia Sidenius Johansen, Mette Klarlund, Ib Lorenzen, Henrik Skjødt, and Mikkel Østergaard.

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Supported by grants from the Danish Rheumatism Association, the Novo Nordisk Foundation, and Research Agency of Slovenia (grant P4-0127 J.K.).

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Jørgensen, I., Kos, J., Krašovec, M. et al. Serum cysteine proteases and their inhibitors in rheumatoid arthritis: relation to disease activity and radiographic progression. Clin Rheumatol 30, 633–638 (2011). https://doi.org/10.1007/s10067-010-1585-1

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  • DOI: https://doi.org/10.1007/s10067-010-1585-1

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