Abstract
Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5–1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs.
References
Baici, A., Camus, A., and Marsich, N. (1984). Interaction of the human leukocyte proteinases elastase and cathepsin G with gold, silver and copper compounds. Biochem. Pharmacol.33, 1859–1865.10.1016/0006-2952(84)90540-9Search in Google Scholar
Barrera, P., Boerbooms, A.M., van de Putte, L.B., and van der Meer, J.W. (1996). Effects of antirheumatic agents on cytokines. Semin. Arthritis Rheum.25, 234–253.10.1016/S0049-0172(96)80035-7Search in Google Scholar
Barrett, A.J., Kembhavi, A.A., Brown, M.A., Kirschke, H., Knight, C.G., Tamai, M., and Hanada, K. (1982). L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L. Biochem. J.201, 189–198.10.1042/bj2010189Search in Google Scholar
Bau, R. (1998). Crystal structure of the antiarthritic drug gold thiomalate (myocrisin): a double-helical geometry in the solid state. J. Am. Chem. Soc.120, 9380–9381.10.1021/ja9819763Search in Google Scholar
Bromme, D. and Okamoto, K. (1995). Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol. Chem. Hoppe-Seyler376, 379–384.10.1515/bchm3.1995.376.6.379Search in Google Scholar
Brömme, D., Okamoto, K., Wang, B.B., and Biroc, S. (1996). Human cathepsin O2, a matrix protein-degrading cysteine protease expressed in osteoclasts. Functional expression of human cathepsin O2 inSpodoptera frugiperda and characterization of the enzyme. J. Biol. Chem.271, 2126–2132.10.1074/jbc.271.4.2126Search in Google Scholar
Bromme, D., Nallaseth, F.S., and Turk, B. (2004). Production and activation of recombinant papain-like cysteine proteases. Methods32, 199–206.10.1016/S1046-2023(03)00212-3Search in Google Scholar
Brune, K. (2003). The molecular basis of novel therapies. In: Inflammation and Rheumatoid Arthritis, S. Laufer, S. Gay and K. Brune, eds. (Stuttgart, New York: Georg Thieme Verlag), pp. 69–92.Search in Google Scholar
Brunger, A.T., Adams, P.D., Clore, G.M., DeLano, W.L., Gros, P., Grosse-Kunstleve, R.W., Jiang, J.S., Kuszewski, J., Nilges, M., Pannu, N.S., et al. (1998). Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr. D Biol. Crystallogr.54, 905–921.10.1107/S0907444998003254Search in Google Scholar PubMed
Chircorian, A. and Barrios, A.M. (2004). Inhibition of lysosomal cysteine proteases by chrysotherapeutic compounds: a possible mechanism for the antiarthritic activity of Au(I). Bioorg. Med. Chem. Lett.14, 5113–5116.10.1016/j.bmcl.2004.07.073Search in Google Scholar PubMed
Conaghan, P.G. and Brooks, P. (1995). Disease-modifying antirheumatic drugs, including methotrexate, gold, antimalarials, and d-penicillamine. Curr. Opin. Rheumatol.7, 167–173.10.1097/00002281-199505000-00003Search in Google Scholar PubMed
Denzin, L.K., Robbins, N.F., Carboy-Newcomb, C., and Cresswell, P. (1994). Assembly and intracellular transport of HLA- DM and correction of the class II antigen-processing defect in T2 cells. Immunity1, 595–606.10.1016/1074-7613(94)90049-3Search in Google Scholar
Doan, T. and Massarotti, E. (2005). Rheumatoid arthritis: an overview of new and emerging therapies. J. Clin. Pharmacol.45, 751–762.10.1177/0091270005277938Search in Google Scholar PubMed
Esser, R.E., Watts, L.M., Angelo, R.A., Thornburg, L.P., Prior, J.J., and Palmer, J.T. (1993). The effects of fluoromethyl ketone inhibitors of cathepsin B on adjuvant-induced arthritis. J. Rheumatol.20, 1176–1183.Search in Google Scholar
Esser, R.E., Angelo, R.A., Murphey, M.D., Watts, L.M., Thornburg, L.P., Palmer, J.T., Talhouk, J.W., and Smith, R.E. (1994). Cysteine proteinase inhibitors decrease articular cartilage and bone destruction in chronic inflammatory arthritis. Arthritis Rheum.37, 236–247.10.1002/art.1780370213Search in Google Scholar PubMed
Everts, V., Aronson, D.C., and Beertsen, W. (1985). Phagocytosis of bone collagen by osteoclasts in two cases of pycnodysostosis. Calcif. Tissue Int.37, 25–31.10.1007/BF02557674Search in Google Scholar PubMed
Everts, V., van der Zee, E., Creemers, L., and Beertsen, W. (1996). Phagocytosis and intracellular digestion of collagen, its role in turnover and remodeling. Histochem. J.28, 229–245.10.1007/BF02409011Search in Google Scholar PubMed
Everts, V., Hou, W.S., Rialland, X., Tigchelaar, W., Saftig, P., Bromme, D., Gelb, B.D., and Beertsen, W. (2003). Cathepsin K deficiency in pycnodysostosis results in accumulation of non-digested phagocytosed collagen in fibroblasts. Calcif. Tissue Int.73, 380–386.10.1007/s00223-002-2092-4Search in Google Scholar PubMed
Felson, D.T., Anderson, J.J., and Meenan, R.F. (1990). The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. >Arthritis Rheum.33, 1449–1461.Search in Google Scholar
Frazer, T. (1945). Gold treatment in rheumatoid arthritis. Ann. Rheum. Dis.4, 71–75.10.1136/ard.4.4.71Search in Google Scholar PubMed PubMed Central
Gelb, B.D., Shi, G.P., Chapman, H.A., and Desnick, R.J. (1996). Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science273, 1236–1238.10.1126/science.273.5279.1236Search in Google Scholar PubMed
Gunatilleke, S.S. and Barrios, A.M. (2006). Inhibition of lysosomal cysteine proteases by a series of Au(I) complexes: a detailed mechanistic investigation. J. Med. Chem.49, 3933–3937.10.1021/jm060158fSearch in Google Scholar PubMed
Hall, T.J., Jeker, H., Nyugen, H., and Schaeublin, M. (1996). Gold salts inhibit osteoclastic bone resorption in vitro. Inflamm. Res.45, 230–233.10.1007/BF02259608Search in Google Scholar PubMed
Hou, W.S., Li, Z., Gordon, R.E., Chan, K., Klein, M.J., Levy, R., Keysser, M., Keyszer, G., and Bromme, D. (2001). Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol.159, 2167–2177.10.1016/S0002-9440(10)63068-4Search in Google Scholar
Hou, W.-S., Li, W., Keyszer, G., Weber, E., Levy, R., Klein, M.J., Gravallese, E.M., Goldring, S.R., and Bromme, D. (2002). Comparison of cathepsins K and S expression within the rheumatoid and osteoarthritic synovium. Arthritis Rheum.46, 663–674.10.1002/art.10114Search in Google Scholar
Kirschke, H., Wiederanders, B., Bromme, D., and Rinne, A. (1989). Cathepsin S from bovine spleen. Purification, distribution, intracellular localization and action on proteins. Biochem. J.264, 467–473.Search in Google Scholar
Kraulis, P.J. (1991). Molscript: a program to produce both detailed and schematic plots of protein structures. J. Appl. Crystallog.24, 157–163.10.1107/S0021889891004399Search in Google Scholar
Laskowski, R.A., MacArthur, M.W., Moss, D.S., and Thornton, J.M. (1993). Procheck: A program to check the stereochemical quality of protein structures. J. Appl. Crystallogr.26, 283–291.10.1107/S0021889892009944Search in Google Scholar
Nakagawa, T.Y., Brissette, W.H., Lira, P.D., Griffiths, R.J., Petrushova, N., Stock, J., McNeish, J.D., Eastman, S.E., Howard, E.D., Clarke, S.R., et al. (1999). Impaired invariant chain degradation and antigen presentation and diminished collagen- induced arthritis in cathepsin S null mice. Immunity10, 207–217.10.1016/S1074-7613(00)80021-7Search in Google Scholar
Palmer, J.T., Rasnick, D., Klaus, J.L., and Brömme, D. (1995). Vinyl sulfones as mechanism-based cysteine protease inhibitors. J. Med. Chem.38, 3193–3196.10.1021/jm00017a002Search in Google Scholar
Punturieri, A., Filippov, S., Allen, E., Caras, I., Murray, R., Reddy, V., and Weiss, S.J. (2000). Regulation of elastinolytic cysteine proteinase activity in normal and cathepsin K-deficient human macrophages. J. Exp. Med.192, 789–800.10.1084/jem.192.6.789Search in Google Scholar
Rau, R., Herborn, G., Menninger, H., and Blechschmidt, J. (1997). Comparison of intramuscular methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis: 12 month data of a double-blind parallel study of 174 patients. Br. J. Rheumatol.36, 345–352.10.1093/rheumatology/36.3.345Search in Google Scholar
Riese, R.J., Wolf, P., Bromme, D., Natkin, L.R., Villadangos, J.A., Ploegh, H.L., and Chapman, H.A. (1996). Essential role for cathepsin S in MHC class II-associated invariant chain processing and peptide loading. Immunity4, 357–366.10.1016/S1074-7613(00)80249-6Search in Google Scholar
Sanders, M. (2000). A review of controlled clinical trials examining the effects of antimalarial compounds and gold compounds on radiographic progression in rheumatoid arthritis. J. Rheumatol.27, 523–529.Search in Google Scholar
Sfikakis, P.P., Souliotis, V.L., Katsilambros, N., Markakis, K., Vaiopoulos, G., Tsokos, G.C., and Panayiotidis, P. (1996). Downregulation of interleukin-2 and α-chain interleukin-2 receptor biosynthesis by cisplatin in human peripheral lymphocytes. Clin. Immunol. Immunopathol.79, 43–49.10.1006/clin.1996.0049Search in Google Scholar PubMed
Simon, L.S. and Yocum, D. (2000). New and future drug therapies for rheumatoid arthritis. Rheumatology (Oxford)3936(Suppl. 1), –42.10.1093/oxfordjournals.rheumatology.a031493Search in Google Scholar PubMed
Xia, L., Kilb, J., Wex, H., Lipyansky, A., Breuil, V., Stein, L., Palmer, J.T., Dempster, D.W., and Brömme, D. (1999). Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption cathepsin K-activity by peptidyl vinyl sulfones. Biol. Chem.380, 679–687.10.1515/BC.1999.084Search in Google Scholar PubMed
Yamashita, M., Ohuchi, K., and Takayanagi, M. (2003). Effects of chrisotherapeutic gold compounds on prostaglandin E2 production. Curr. Drug Targets Inflamm. Allergy2, 216–223.10.2174/1568010033484142Search in Google Scholar PubMed
Yasuda, Y., Kaleta, J., and Brömme, D. (2005). The role of cathepsins in osteoporosis and arthritis: rationale for the design of new therapeutics. Adv. Drug Deliv. Rev.25, 973–993.10.1016/j.addr.2004.12.013Search in Google Scholar PubMed
©2007 by Walter de Gruyter Berlin New York