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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


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Volume 394, Issue 9

Issues

Cathepsin K: a unique collagenolytic cysteine peptidase

Marko Novinec
  • Corresponding author
  • Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
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/ Brigita Lenarčič
  • Corresponding author
  • Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
  • Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia
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Published Online: 2013-04-27 | DOI: https://doi.org/10.1515/hsz-2013-0134

Abstract

Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation.

Keywords: allostery; collagen; cysteine peptidase; glycosaminoglycan; osteoporosis; proteolysis

References

  • Abdollahi-Roodsaz, S., Joosten, L.A., Koenders, M.I., van den Brand, B.T., van de Loo, F.A., and van den Berg, W.B. (2009). Local interleukin-1-driven joint pathology is dependent on toll-like receptor 4 activation. Am. J. Pathol. 175, 2004–2013.Google Scholar

  • Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., and Walter, P. (2002). Molecular Biology of the Cell, 4th Edition (New York, NY, USA: Garland Science).Google Scholar

  • Alves, M.F., Puzer, L., Cotrin, S.S., Juliano, M.A., Juliano, L., Brömme, D., and Carmona, A.K. (2003). S3 to S3’ subsite specificity of recombinant human cathepsin K and development of selective internally quenched fluorescent substrates. Biochem. J. 373, 981–986.Google Scholar

  • Asagiri, M., Hirai, T., Kunigami, T., Kamano, S., Gober, H.J., Okamoto, K., Nishikawa, K., Latz, E., Golenbock, D.T., Aoki, K., et al. (2008). Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science 319, 624–627.Google Scholar

  • Atley, L.M., Mort, J.S., Lalumiere, M., and Eyre, D.R. (2000). Proteolysis of human bone collagen by cathepsin K: characterization of the cleavage sites generating by cross-linked N-telopeptide neoepitope. Bone 26, 241–247.CrossrefPubMedGoogle Scholar

  • Avila, J.L. and Convit, J. (1975). Inhibition of leucocytic lysosomal enzymes by glycosaminoglycans in vitro. Biochem. J. 152, 57–64.Google Scholar

  • Barrett, A.J. (1986). The cystatins: a diverse superfamily of cysteine peptidase inhibitors. Biomed. Biochim. Acta 45, 1363–1374.PubMedGoogle Scholar

  • Bernstein, H.G., Bukowska, A., Dobrowolny, H., Bogerts, B., and Lendeckel, U. (2007). Cathepsin K and schizophrenia. Synapse 61, 252–253.CrossrefPubMedGoogle Scholar

  • Bone, H. (2012). Future directions in osteoporosis therapeutics. Endocrinol. Metab. Clin. North. Am. 41, 655–661.Google Scholar

  • Boonen, S., Rosenberg, E., Claessens, F., Vanderschueren, D., and Papapoulos, S. (2012). Inhibition of cathepsin K for treatment of osteoporosis. Curr. Osteoporos. Rep. 10, 73–79.PubMedCrossrefGoogle Scholar

  • Borel, O., Gineyts, E., Bertholon, C., and Garnero, P. (2012). Cathepsin K preferentially solubilizes matured bone matrix. Calcif. Tissue Int. 91, 32–39.Google Scholar

  • Bossard, M.J., Tomaszek, T.A., Thompson, S.K., Amegadzie, B.Y., Hanning, C.R., Jones, C., Kurdyla, J.T., McNulty, D.E., Drake, F.H., Gowen, M., et al. (1996). Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J. Biol. Chem. 271, 12517–12524.Google Scholar

  • Brage, M., Abrahamson, M., Lindstrom, V., Grubb, A., and Lerner, U.H. (2005). Different cysteine proteinases involved in bone resorption and osteoclast formation. Calcif. Tissue Int. 76, 439–447.CrossrefPubMedGoogle Scholar

  • Brix, K., Dunkhorst, A., Mayer, K., and Jordans, S. (2008). Cysteine cathepsins: cellular roadmap to different functions. Biochimie 90, 194–207.CrossrefPubMedGoogle Scholar

  • Brömme, D. and Lecaille, F. (2009). Cathepsin K inhibitors for osteoporosis and potential off-target effects. Expert. Opin. Investig. Drugs 18, 585–600.PubMedCrossrefGoogle 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 in Spodoptera frugiperda and characterization of the enzyme. J. Biol. Chem. 271, 2126–2132.Google Scholar

  • Bühling, F., Rocken, C., Brasch, F., Hartig, R., Yasuda, Y., Saftig, P., Brömme, D., and Welte, T. (2004). Pivotal role of cathepsin K in lung fibrosis. Am. J. Pathol. 16, 2203–2216.CrossrefGoogle Scholar

  • Caglič, D., Pungerčar, J.R., Pejler, G., Turk, V., and Turk, B. (2007). Glycosaminoglycans facilitate procathepsin B activation through disruption of propeptide-mature enzyme interactions. J. Biol. Chem. 282, 33076–33085.Google Scholar

  • Charni-Ben Tabassi, N., Desmarais, S., Bay-Jensen, A.C., Delaisse, J.M., Percival, M.D., and Garnero, P. (2008). The type II collagen fragments Helix-II and CTX-II reveal different enzymatic pathways of human cartilage collagen degradation. Osteoarthritis Cartilage 16, 1183–1191.Google Scholar

  • Cherney, M.M., Lecaille, F., Kienitz, M., Nallaseth, F.S., Li, Z., James, M.N., and Brömme, D. (2011). Structure-activity analysis of cathepsin K/chondroitin 4-sulfate interactions. J. Biol. Chem. 286, 8988–8998.Google Scholar

  • Chiellini, C., Costa, M., Novelli, S.E., Amri, E.Z., Benzi, L., Bertacca, A., Cohen, P., Del Prato, S., Friedman, J.M., and Maffei, M. (2003). Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J. Cell. Physiol. 195, 309–321.Google Scholar

  • Chiodoni, C., Colombo, M.P., and Sangaletti, S. (2010). Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev. 29, 295–307.Google Scholar

  • Choe, Y., Leonetti, F., Greenbaum, D.C., Lecaille, F., Bogyo, M., Brömme, D., Ellman, J.A., and Craik, C.S. (2006). Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities. J. Biol. Chem. 281, 12824–12832.Google Scholar

  • Chung, L., Dinakarpandian, D., Yoshida, N., Lauer-Fields, J.L., Fields, G.B., Visse, R., and Nagase, H. (2004). Collagenase unwinds triple-helical collagen prior to peptide bond hydrolysis. EMBO J. 23, 3020–3030.Google Scholar

  • Clemens, J.D., Herrick, M.V., Singer, F.R., and Eyre, D.R. (1997). Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption. Clin. Chem. 43, 2058–2063.Google Scholar

  • Cordes, C., Bartling, B., Simm, A., Afar, D., Lautenschlager, C., Hansen, G., Silber, R.E., Burdach, S., and Hofmann, H.S. (2009). Simultaneous expression of Cathepsins B and K in pulmonary adenocarcinomas and squamous cell carcinomas predicts poor recurrence-free and overall survival. Lung Cancer 64, 79–85.Google Scholar

  • Dauth, S., Sirbulescu, R.F., Jordans, S., Rehders, M., Avena, L., Oswald, J., Lerchl, A., Saftig, P., and Brix, K. (2011). Cathepsin K deficiency in mice induces structural and metabolic changes in the central nervous system that are associated with learning and memory deficits. BMC Neurosci. 12, 74.PubMedCrossrefGoogle Scholar

  • Dejica, V.M., Mort, J.S., Laverty, S., Antoniou, J., Zukor, D.J., Tanzer, M., and Poole, A.R. (2008). Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage. Am. J. Pathol. 173, 161–169.Google Scholar

  • Dejica, V.M., Mort, J.S., Laverty, S., Percival, M.D., Antoniou, J., Zukor, D.J., and Poole, A.R. (2012). Increased type II collagen cleavage by cathepsin K and collagenase activities with aging and osteoarthritis in human articular cartilage. Arthritis Res. Ther. 14, R113.CrossrefGoogle Scholar

  • Donnarumma, M., Regis, S., Tappino, B., Rosano, C., Assereto, S., Corsolini, F., Di Rocco, M., and Filocamo, M. (2007). Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Mutation in brief #961. Online. Hum. Mutat. 28, 524.Google Scholar

  • Dubin, G. (2005). Proteinaceous cysteine protease inhibitors. Cell Mol. Life Sci. 62, 653–669.PubMedCrossrefGoogle Scholar

  • Eisman, J.A., Bone, H.G., Hosking, D.J., McClung, M.R., Reid, I.R., Rizzoli, R., Resch, H., Verbruggen, N., Hustad, C.M., DaSilva, C., et al. (2011). Odanacatib in the treatment of postmenopausal women with low bone mineral density: three-year continued therapy and resolution of effect. J. Bone Miner. Res. 26, 242–251.CrossrefGoogle Scholar

  • 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.CrossrefPubMedGoogle Scholar

  • Everts, V., Delaisse, J.M., Korper, W., Jansen, D.C., Tigchelaar-Gutter, W., Saftig, P., and Beertsen, W. (2002). The bone lining cell: its role in cleaning Howship’s lacunae and initiating bone formation. J. Bone Miner. Res. 17, 77–90.CrossrefGoogle Scholar

  • Falgueyret, J.P., Desmarais, S., Oballa, R., Black, W.C., Cromlish, W., Khougaz, K., Lamontagne, S., Masse, F., Riendeau, D., Toulmond, S., et al. (2005). Lysosomotropism of basic cathepsin K inhibitors contributes to increased cellular potencies against off-target cathepsins and reduced functional selectivity. J. Med. Chem. 48, 7535–7543.CrossrefGoogle Scholar

  • Funicello, M., Novelli, M., Ragni, M., Vottari, T., Cocuzza, C., Soriano-Lopez, J., Chiellini, C., Boschi, F., Marzola, P., Masiello, P., et al. (2007). Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores. PLoS One 2, e683.Google Scholar

  • Garnero, P., Borel, O., Byrjalsen, I., Ferreras, M., Drake, F.H., McQueney, M.S., Foged, N.T., Delmas, P.D., and Delaisse, J.M. (1998). The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J. Biol. Chem. 273, 32347–32352.Google Scholar

  • Garnero, P., Ferreras, M., Karsdal, M.A., Nicamhlaoibh, R., Risteli, J., Borel, O., Qvist, P., Delmas, P.D., Foged, N.T., and Delaisse, J.M. (2003). The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation. J. Bone Miner. Res. 18, 859–867.CrossrefGoogle Scholar

  • Gauthier, J.Y., Chauret, N., Cromlish, W., Desmarais, S., Duong le, T., Falgueyret, J.P., Kimmel, D.B., Lamontagne, S., Leger, S., LeRiche, T., et al. (2008). The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg. Med. Chem. Lett. 18, 923–928.Google Scholar

  • Gelb, B.D., Shi, G.P., Chapman, H.A., and Desnick, R.J. (1996). Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273, 1236–1238.Google Scholar

  • Giraudeau, F.S., McGinnis, R.E., Gray, I.C., O’Brien, E.J., Doncaster, K.E., Spurr, N.K., Ralston, S.H., Reid, D.M., and Wood, J. (2004). Characterization of common genetic variants in cathepsin K and testing for association with bone mineral density in a large cohort of perimenopausal women from Scotland. J. Bone Miner. Res. 19, 31–41.Google Scholar

  • Godat, E., Herve-Grvepinet, V., Veillard, F., Lecaille, F., Belghazi, M., Bromme, D., and Lalmanach, G. (2008). Regulation of cathepsin K activity by hydrogen peroxide. Biol. Chem. 389, 1123–1126.Google Scholar

  • Haeckel, C., Krueger, S., Buehling, F., Broemme, D., Franke, K., Schuetze, A., Roese, I., and Roessner, A. (1999). Expression of cathepsin K in the human embryo and fetus. Dev. Dyn. 216, 89–95.Google Scholar

  • Han, J., Luo, T., Gu, Y., Li, G., Jia, W., and Luo, M. (2009). Cathepsin K regulates adipocyte differentiation: possible involvement of type I collagen degradation. Endocr. J. 56, 55–63.CrossrefPubMedGoogle Scholar

  • Hanson, D.A., Weis, M.A., Bollen, A.M., Maslan, S.L., Singer, F.R., and Eyre, D.R. (1992). A specific immunoassay for monitoring human bone resorption: quantitation of type I collagen cross-linked N-telopeptides in urine. J. Bone Miner. Res. 7, 1251–1258.Google Scholar

  • Helske, S., Syvaranta, S., Lindstedt, K.A., Lappalainen, J., Oorni, K., Mayranpaa, M.I., Lommi, J., Turto, H., Werkkala, K., Kupari, M., et al. (2006). Increased expression of elastolytic cathepsins S, K, and V and their inhibitor cystatin C in stenotic aortic valves. Arterioscler. Thromb. Vasc. Biol. 26, 1791–1798.PubMedGoogle Scholar

  • Herroon, M.K., Rajagurubandara, E., Rudy, D.L., Chalasani, A., Hardaway, A.L., and Podgorski, I. (2012). Macrophage cathepsin K promotes prostate tumor progression in bone. Oncogene 32, 1580–1593.PubMedGoogle Scholar

  • Herve-Grepinet, V., Veillard, F., Godat, E., Heuze-Vourc’h, N., Lecaille, F., and Lalmanach, G. (2008). Extracellular catalase activity protects cysteine cathepsins from inactivation by hydrogen peroxide. FEBS Lett. 582, 1307–1312.Google Scholar

  • Hirabara, S., Kojima, T., Takahashi, N., Hanabayashi, M., and Ishiguro, N. (2013). Hyaluronan inhibits TLR-4 dependent cathepsin K and matrix metalloproteinase 1 expression in human fibroblasts. Biochem. Biophys. Res. Commun. 430, 519–522.Google Scholar

  • Hou, W.S., Brömme, D., Zhao, Y., Mehler, E., Dushey, C., Weinstein, H., Miranda, C.S., Fraga, C., Greig, F., Carey, J., et al. (1999). Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. J. Clin. Invest. 103, 731–738.Google Scholar

  • Hou, W.S., Li, Z., Buttner, F.H., Bartnik, E., and Brömme, D. (2003). Cleavage site specificity of cathepsin K toward cartilage proteoglycans and protease complex formation. Biol. Chem. 384, 891–897.Google Scholar

  • Hou, W.S., Li, Z., Gordon, R.E., Chan, K., Klein, M.J., Levy, R., Keysser, M., Keyszer, G., and Brömme, D. (2001). Cathepsin K is a critical protease in synovial fibroblast-mediated collagen degradation. Am. J. Pathol. 159, 2167–2177.Google Scholar

  • Husmann, K., Muff, R., Bolander, M.E., Sarkar, G., Born, W., and Fuchs, B. (2008). Cathepsins and osteosarcoma: Expression analysis identifies cathepsin K as an indicator of metastasis. Mol. Carcinog. 47, 66–73.Google Scholar

  • Inaoka, T., Bilbe, G., Ishibashi, O., Tezuka, K., Kumegawa, M., and Kokubo, T. (1995). Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem. Biophys. Res. Commun. 206, 89–96.Google Scholar

  • Inui, T., Ishibashi, O., Inaoka, T., Origane, Y., Kumegawa, M., Kokubo, T., and Yamamura, T. (1997). Cathepsin K antisense oligodeoxynucleotide inhibits osteoclastic bone resorption. J. Biol. Chem. 272, 8109–8112.Google Scholar

  • Ishibashi, O., Mori, Y., Kurokawa, T., and Kumegawa, M. (1999). Breast cancer cells express cathepsins B and L but not cathepsins K or H. Cancer Biochem. Biophys. 17, 69–78.PubMedGoogle Scholar

  • Ishidoh, K. and Kominami, E. (1995). Procathepsin L degrades extracellular matrix proteins in the presence of glycosaminoglycans in vitro. Biochem. Biophys. Res. Commun. 217, 624–631.Google Scholar

  • Jensen, A.B., Wynne, C., Ramirez, G., He, W., Song, Y., Berd, Y., Wang, H., Mehta, A., and Lombardi, A. (2010). The cathepsin K inhibitor odanacatib suppresses bone resorption in women with breast cancer and established bone metastases: results of a 4-week, double-blind, randomized, controlled trial. Clin. Breast Cancer 10, 452–458.CrossrefGoogle Scholar

  • Jordans, S., Jenko-Kokalj, S., Kuhl, N.M., Tedelind, S., Sendt, W., Brömme, D., Turk, D., and Brix, K. (2009). Monitoring compartment-specific substrate cleavage by cathepsins B, K, L, and S at physiological pH and redox conditions. BMC Biochem. 10, 23.CrossrefGoogle Scholar

  • Kafienah, W., Brömme, D., Buttle, D.J., Croucher, L.J., and Hollander, A.P. (1998a). Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem. J. 331, 727–732.Google Scholar

  • Kafienah, W., Buttle, D.J., Burnett, D., and Hollander, A.P. (1998b). Cleavage of native type I collagen by human neutrophil elastase. Biochem. J. 330, 897–902.Google Scholar

  • Kim, K.W., Cho, M.L., Oh, H.J., Kim, H.R., Kang, C.M., Heo, Y.M., Lee, S.H., and Kim, H.Y. (2009). TLR-3 enhances osteoclastogenesis through upregulation of RANKL expression from fibroblast-like synoviocytes in patients with rheumatoid arthritis. Immunol. Lett. 124, 9–17.Google Scholar

  • Ko, F., Tallerico, T., and Seeman, P. (2006). Antipsychotic pathway genes with expression altered in opposite direction by antipsychotics and amphetamine. Synapse 60, 141–151.PubMedCrossrefGoogle Scholar

  • Kumar, S., Dare, L., Vasko-Moser, J.A., James, I.E., Blake, S.M., Rickard, D.J., Hwang, S.M., Tomaszek, T., Yamashita, D.S., Marquis, R.W., et al. (2007). A highly potent inhibitor of cathepsin K (relacatib) reduces biomarkers of bone resorption both in vitro and in an acute model of elevated bone turnover in vivo in monkeys. Bone 40, 122–131.CrossrefGoogle Scholar

  • Kylmala, T., Tammela, T.L., Risteli, L., Risteli, J., Kontturi, M., and Elomaa, I. (1995). Type I collagen degradation product (ICTP) gives information about the nature of bone metastases and has prognostic value in prostate cancer. Br. J. Cancer 71, 1061–1064.Google Scholar

  • Lafarge, J.C., Naour, N., Clement, K., and Guerre-Millo, M. (2010). Cathepsins and cystatin C in atherosclerosis and obesity. Biochimie 92, 1580–1586.CrossrefPubMedGoogle Scholar

  • Langdahl, B., Binkley, N., Bone, H., Gilchrist, N., Resch, H., Rodriguez Portales, J., Denker, A., Lombardi, A., Le Bailly De Tilleghem, C., et al. (2012). Odanacatib in the treatment of postmenopausal women with low bone mineral density: Five years of continued therapy in a phase 2 study. J. Bone Miner. Res. 27, 2251–2258.CrossrefGoogle Scholar

  • Lange, A.W. and Yutzey, K.E. (2006). NFATc1 expression in the developing heart valves is responsive to the RANKL pathway and is required for endocardial expression of cathepsin K. Dev. Biol. 292, 407–417.Google Scholar

  • Lecaille, F., Brömme, D., and Lalmanach, G. (2008). Biochemical properties and regulation of cathepsin K activity. Biochimie 90, 208–226.CrossrefPubMedGoogle Scholar

  • Lecaille, F., Choe, Y., Brandt, W., Li, Z., Craik, C.S., and Brömme, D. (2002). Selective inhibition of the collagenolytic activity of human cathepsin K by altering its S2 subsite specificity. Biochemistry 41, 8447–8454.CrossrefGoogle Scholar

  • Lecaille, F., Weidauer, E., Juliano, M.A., Brömme, D., and Lalmanach, G. (2003). Probing cathepsin K activity with a selective substrate spanning its active site. Biochem. J. 375, 307–312.Google Scholar

  • Lenarčič, B. and Bevec, T. (1998). Thyropins–new structurally related proteinase inhibitors. Biol. Chem. 379, 105–111.Google Scholar

  • Lendeckel, U., Kahne, T., Ten Have, S., Bukowska, A., Wolke, C., Bogerts, B., Keilhoff, G., and Bernstein, H.G. (2009). Cathepsin K generates enkephalin from beta-endorphin: a new mechanism with possible relevance for schizophrenia. Neurochem. Int. 54, 410–417.Google Scholar

  • Li, Z., Hou, W.S., and Brömme, D. (2000). Collagenolytic activity of cathepsin K is specifically modulated by cartilage-resident chondroitin sulfates. Biochemistry 39, 529–536.PubMedCrossrefGoogle Scholar

  • Li, Z., Hou, W.S., Escalante-Torres, C.R., Gelb, B.D., and Brömme, D. (2002). Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. J. Biol. Chem. 277, 28669–28676.Google Scholar

  • Li, Z., Kienetz, M., Cherney, M.M., James, M.N., and Brömme, D. (2008). The crystal and molecular structures of a cathepsin K:chondroitin sulfate complex. J. Mol. Biol. 383, 78–91.Google Scholar

  • Li, Z., Yasuda, Y., Li, W., Bogyo, M., Katz, N., Gordon, R.E., Fields, G.B., and Brömme, D. (2004). Regulation of collagenase activities of human cathepsins by glycosaminoglycans. J. Biol. Chem. 279, 5470–5479.Google Scholar

  • Lindeman, J.H., Hanemaaijer, R., Mulder, A., Dijkstra, P.D., Szuhai, K., Brömme, D., Verheijen, J.H., and Hogendoorn, P.C. (2004). Cathepsin K is the principal protease in giant cell tumor of bone. Am. J. Pathol. 165, 593–600.Google Scholar

  • Lippuner, K. (2012). The future of osteoporosis treatment – a research update. Swiss Med. Wkly. 142, w13624.Google Scholar

  • Littlewood-Evans, A.J., Bilbe, G., Bowler, W.B., Farley, D., Wlodarski, B., Kokubo, T., Inaoka, T., Sloane, J., Evans, D.B., and Gallagher, J.A. (1997). The osteoclast-associated protease cathepsin K is expressed in human breast carcinoma. Cancer Res. 57, 5386–5390.Google Scholar

  • Lutgens, E., Lutgens, S.P., Faber, B.C., Heeneman, S., Gijbels, M.M., de Winther, M.P., Frederik, P., van der Made, I., Daugherty, A., Sijbers, A.M., et al. (2006a). Disruption of the cathepsin K gene reduces atherosclerosis progression and induces plaque fibrosis but accelerates macrophage foam cell formation. Circulation 113, 98–107.Google Scholar

  • Lutgens, S.P., Kisters, N., Lutgens, E., van Haaften, R.I., Evelo, C.T., de Winther, M.P., Saftig, P., Daemen, M.J., Heeneman, S., and Cleutjens, K.B. (2006b). Gene profiling of cathepsin K deficiency in atherogenesis: profibrotic but lipogenic. J. Pathol. 210, 334–343.Google Scholar

  • Mason, R.W. and Massey, S.D. (1992). Surface activation of pro-cathepsin L. Biochem. Biophys. Res. Commun. 189, 1659–1666.Google Scholar

  • McGrath, M.E., Klaus, J.L., Barnes, M.G., and Brömme, D. (1997). Crystal structure of human cathepsin K complexed with a potent inhibitor. Nat. Struct. Biol. 4, 105–109.CrossrefPubMedGoogle Scholar

  • Mihelič, M., Doberšek, A., Gunčar, G., and Turk, D. (2008). Inhibitory fragment from the p41 form of invariant chain can regulate activity of cysteine cathepsins in antigen presentation. J. Biol. Chem. 283, 14453–14460.Google Scholar

  • Mohamed, M.M. and Sloane, B.F. (2006). Cysteine cathepsins: multifunctional enzymes in cancer. Nat. Rev. Cancer 6, 764–775.PubMedCrossrefGoogle Scholar

  • Nagase, S., Hashimoto, Y., Small, M., Ohyama, M., Kuwayama, T., and Deacon, S. (2012a). Serum and urine bone resorption markers and pharmacokinetics of the cathepsin K inhibitor ONO-5334 after ascending single doses in post menopausal women. Br. J. Clin. Pharmacol. 74, 959–970.CrossrefGoogle Scholar

  • Nagase, S., Ohyama, M., Hashimoto, Y., Small, M., Kuwayama, T., and Deacon, S. (2012b). Pharmacodynamic effects on biochemical markers of bone turnover and pharmacokinetics of the cathepsin K inhibitor, ONO-5334, in an ascending multiple-dose, phase 1 study. J. Clin. Pharmacol. 52, 306–318.Google Scholar

  • Novinec, M., Grass, R.N., Stark, W.J., Turk, V., Baici, A., and Lenarčič, B. (2007). Interaction between human cathepsins K, L, and S and elastins: mechanism of elastinolysis and inhibition by macromolecular inhibitors. J. Biol. Chem. 282, 7893–7902.Google Scholar

  • Novinec, M., Kovačič, L., Lenarčič, B., and Baici, A. (2010). Conformational flexibility and allosteric regulation of cathepsin K. Biochem. J. 429, 379–389.Google Scholar

  • Novinec, M., Lenarčič, B., and Baici, A. (2012). Clusterin is a specific stabilizer and liberator of extracellular cathepsin K. FEBS Lett. 586, 1062–1066.Google Scholar

  • Ochi, Y., Yamada, H., Mori, H., Nakanishi, Y., Nishikawa, S., Kayasuga, R., Kawada, N., Kunishige, A., Hashimoto, Y., Tanaka, M., et al. (2011). Effects of ONO-5334, a novel orally-active inhibitor of cathepsin K, on bone metabolism. Bone 49, 1351–1356.Google Scholar

  • Oliveira, M., Assis, D.M., Paschoalin, T., Miranda, A., Ribeiro, E.B., Juliano, M.A., Brömme, D., Christoffolete, M.A., Barros, N.M., and Carmona, A.K. (2012). Cysteine cathepsin S processes leptin, inactivating its biological activity. J. Endocrinol. 214, 217–224.Google Scholar

  • Podgorski, I., Linebaugh, B.E., Koblinski, J.E., Rudy, D.L., Herroon, M.K., Olive, M.B., and Sloane, B.F. (2009). Bone marrow-derived cathepsin K cleaves SPARC in bone metastasis. Am. J. Pathol. 175, 1255–1269.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, 789–799.Google Scholar

  • Quintanilla-Dieck, M.J., Codriansky, K., Keady, M., Bhawan, J., and Rünger, T.M. (2008). Cathepsin K in melanoma invasion. J. Invest. Dermatol. 128, 2281–2288.Google Scholar

  • Rapa, I., Volante, M., Cappia, S., Rosas, R., Scagliotti, G.V., and Papotti, M. (2006). Cathepsin K is selectively expressed in the stroma of lung adenocarcinoma but not in bronchioloalveolar carcinoma. A useful marker of invasive growth. Am. J. Clin. Pathol. 125, 847–854.Google Scholar

  • Rawlings, N.D., Barrett, A.J., and Bateman, A. (2012). MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 40, D343–350.CrossrefGoogle Scholar

  • Rawlings, N.D., Tolle, D.P., and Barrett, A.J. (2004). Evolutionary families of peptidase inhibitors. Biochem. J. 378, 705–716.Google Scholar

  • Ricard-Blum, S. (2011). The collagen family. Cold Spring Harb. Perspect. Biol. 3, a004978.Google Scholar

  • Risteli, J., Elomaa, I., Niemi, S., Novamo, A., and Risteli, L. (1993). Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin. Chem. 39, 635–640.Google Scholar

  • Rosen, H.N., Moses, A.C., Garber, J., Iloputaife, I.D., Ross, D.S., Lee, S.L., and Greenspan, S.L. (2000). Serum CTX: a new marker of bone resorption that shows treatment effect more often than other markers because of low coefficient of variability and large changes with bisphosphonate therapy. Calcif. Tissue Int. 66, 100–103.Google Scholar

  • Rünger, T.M., Adami, S., Benhamou, C.L., Czerwinski, E., Farrerons, J., Kendler, D.L., Mindeholm, L., Realdi, G., Roux, C., and Smith, V. (2012). Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib. J. Am. Acad. Dermatol. 66, e89–96.Google Scholar

  • Saftig, P., Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W., Moritz, J.D., Schu, P., and von Figura, K. (1998). Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc. Natl. Acad. Sci. USA 95, 13453–13458.Google Scholar

  • Samokhin, A.O., Wong, A., Saftig, P., and Brömme, D. (2008). Role of cathepsin K in structural changes in brachiocephalic artery during progression of atherosclerosis in apoE-deficient mice. Atherosclerosis 200, 58–68.Google Scholar

  • Sassi, M.L., Eriksen, H., Risteli, L., Niemi, S., Mansell, J., Gowen, M., and Risteli, J. (2000). Immunochemical characterization of assay for carboxyterminal telopeptide of human type I collagen: loss of antigenicity by treatment with cathepsin K. Bone 26, 367–373.CrossrefPubMedGoogle Scholar

  • Schilling, O. and Overall, C.M. (2008). Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. Nat. Biotechnol. 26, 685–694.CrossrefPubMedGoogle Scholar

  • Schuiling, K.D., Robinia, K., and Nye, R. (2011). Osteoporosis update. J. Midwifery Womens Health 56, 615–627.CrossrefGoogle Scholar

  • Skrzydlewska, E., Sulkowska, M., Koda, M., and Sulkowski, S. (2005). Proteolytic-antiproteolytic balance and its regulation in carcinogenesis. World J. Gastroenterol. 11, 1251–1266.Google Scholar

  • Spiegelman, B.M. and Ginty, C.A. (1983). Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35, 657–666.Google Scholar

  • Stoch, S.A., Zajic, S., Stone, J.A., Miller, D.L., van Bortel, L., Lasseter, K.C., Pramanik, B., Cilissen, C., Liu, Q., Liu, L., et al. (2012). Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: Safety, tolerability, pharmacokinetics and pharmacodynamics – Results from single oral dose studies in healthy volunteers. Br. J. Clin. Pharmacol. 75, 1240–1254.Google Scholar

  • Stumptner-Cuvelette, P. and Benaroch, P. (2002). Multiple roles of the invariant chain in MHC class II function. Biochim. Biophys. Acta 1542, 1–13.Google Scholar

  • Sukhova, G.K., Shi, G.P., Simon, D.I., Chapman, H.A., and Libby, P. (1998). Expression of the elastolytic cathepsins S and K in human atheroma and regulation of their production in smooth muscle cells. J. Clin. Invest. 102, 576–583.CrossrefGoogle Scholar

  • Suoranta, S., Manninen, H., Koskenkorva, P., Kononen, M., Laitinen, R., Lehesjoki, A.E., Kalviainen, R., and Vanninen, R. (2012). Thickened skull, scoliosis and other skeletal findings in Unverricht-Lundborg disease link cystatin B function to bone metabolism. Bone 51, 1016–1024.Google Scholar

  • Taleb, S. and Clement, K. (2007). Emerging role of cathepsin S in obesity and its associated diseases. Clin. Chem. Lab. Med. 45, 328–332.Google Scholar

  • Tepel, C., Brömme, D., Herzog, V., and Brix, K. (2000). Cathepsin K in thyroid epithelial cells: sequence, localization and possible function in extracellular proteolysis of thyroglobulin. J. Cell Sci. 113, 4487–4498.Google Scholar

  • Tezuka, K., Tezuka, Y., Maejima, A., Sato, T., Nemoto, K., Kamioka, H., Hakeda, Y., and Kumegawa, M. (1994). Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J. Biol. Chem. 269, 1106–1109.Google Scholar

  • Turk, B., Turk, D., and Salvesen, G.S. (2002). Regulating cysteine protease activity: essential role of protease inhibitors as guardians and regulators. Curr. Pharm. Des. 8, 1623–1637.PubMedCrossrefGoogle Scholar

  • Turk, D., Gunčar, G., Podobnik, M., and Turk, B. (1998). Revised definition of substrate binding sites of papain-like cysteine proteases. Biol. Chem. 379, 137–147.Google Scholar

  • Turk, V., Stoka, V., Vasiljeva, O., Renko, M., Sun, T., Turk, B., and Turk, D. (2012). Cysteine cathepsins: from structure, function and regulation to new frontiers. Biochim. Biophys. Acta 1824, 68–88.Google Scholar

  • Vargova, V., Pytliak, M., and Mechirova, V. (2012). Matrix metalloproteinases. EXS 103, 1–33.PubMedGoogle Scholar

  • Vasiljeva, O., Dolinar, M., Pungerčar, J.R., Turk, V., and Turk, B. (2005). Recombinant human procathepsin S is capable of autocatalytic processing at neutral pH in the presence of glycosaminoglycans. FEBS Lett. 579, 1285–1290.Google Scholar

  • Velasco, G., Ferrando, A.A., Puente, X.S., Sanchez, L.M., and Lopez-Otin, C. (1994). Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues. J. Biol. Chem. 269, 27136–27142.Google Scholar

  • Votta, B.J., Levy, M.A., Badger, A., Bradbeer, J., Dodds, R.A., James, I.E., Thompson, S., Bossard, M.J., Carr, T., Connor, J.R., et al. (1997). Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J. Bone Miner. Res. 12, 1396–1406.CrossrefGoogle Scholar

  • Wijkmans, J. and Gossen, J. (2011). Inhibitors of cathepsin K: a patent review (2004–2010). Expert Opin. Ther. Pat. 21, 1611–1629.Google Scholar

  • Williams, S.C. (2012). Potential first-in-class osteoporosis drug speeds through trials. Nat. Med. 18, 1158.CrossrefPubMedGoogle Scholar

  • Wilson, S., Hashamiyan, S., Clarke, L., Saftig, P., Mort, J., Dejica, V.M., and Brömme, D. (2009). Glycosaminoglycan-mediated loss of cathepsin K collagenolytic activity in MPS I contributes to osteoclast and growth plate abnormalities. Am. J. Pathol. 175, 2053–2062.Google Scholar

  • Xie, L., Moroi, Y., Hayashida, S., Tsuji, G., Takeuchi, S., Shan, B., Nakahara, T., Uchi, H., Takahara, M., and Furue, M. (2011). Cathepsin K-upregulation in fibroblasts promotes matrigel invasive ability of squamous cell carcinoma cells via tumor-derived IL-1alpha. J. Dermatol. Sci. 61, 45–50.Google Scholar

  • Xue, Y., Cai, T., Shi, S., Wang, W., Zhang, Y., Mao, T., and Duan, X. (2011). Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet J. Rare Dis. 6, 20.Google Scholar

  • Yan, X., Takahara, M., Xie, L., Oda, Y., Nakahara, T., Uchi, H., Takeuchi, S., Tu, Y., Moroi, Y., and Furue, M. (2011). Stromal expression of cathepsin K in squamous cell carcinoma. J. Eur. Acad. Dermatol. Venereol. 25, 362–365.Google Scholar

  • Yang, M., Sun, J., Zhang, T., Liu, J., Zhang, J., Shi, M.A., Darakhshan, F., Guerre-Millo, M., Clement, K., Gelb, B.D., et al. (2008). Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice. Arterioscler. Thromb. Vasc. Biol. 28, 2202–2208.PubMedGoogle Scholar

  • Yang, M., Zhang, Y., Pan, J., Sun, J., Liu, J., Libby, P., Sukhova, G.K., Doria, A., Katunuma, N., Peroni, O.D., et al. (2007). Cathepsin L activity controls adipogenesis and glucose tolerance. Nat. Cell Biol. 9, 970–977.PubMedGoogle Scholar

  • Yasuda, Y., Li, Z., Greenbaum, D., Bogyo, M., Weber, E., and Brömme, D. (2004). Cathepsin V, a novel and potent elastolytic activity expressed in activated macrophages. J. Biol. Chem. 279, 36761–36770.Google Scholar

  • Zhang, S.H., Reddick, R.L., Piedrahita, J.A., and Maeda, N. (1992). Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468–471.Google Scholar

  • Zhao, B., Janson, C.A., Amegadzie, B.Y., D’Alessio, K., Griffin, C., Hanning, C.R., Jones, C., Kurdyla, J., McQueney, M., Qiu, X., et al. (1997). Crystal structure of human osteoclast cathepsin K complex with E-64. Nat. Struct. Biol. 4, 109–111.CrossrefGoogle Scholar

About the article

Marko Novinec

Marko Novinec did his PhD studies at the Jožef Stefan Institute, Ljubljana, Slovenia and received a PhD in Biomedicine from the University of Ljubljana, Slovenia in 2008. He continued his training as a Postdoc in the group of Prof. Antonio Baici at the University of Zürich, Switzerland, where he investigated the mechanisms of allosteric regulation in cysteine peptidases. Since 2013, he is Assistant Professor of Biochemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. His research focuses on the structure-function-evolution relationships in enzymes.

Brigita Lenarčič

Brigita Lenarčič holds a BSc in Pharmacy and a PhD in Chemistry from the University of Ljubljana, Slovenia. She was a guest scientist at the University of Notre Dame, Indiana, USA and Sincrotrone Trieste, Italy. She works as a senior researcher at the Jožef Stefan Institute, Ljubljana, Slovenia. Since 2006 she is Professor of Biochemistry and Head of the Chair of Biochemistry at the Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia. Her research focuses on the structure-function relationships in extracellular matrix proteins and regulation of peptidase activity.


Corresponding authors: Marko Novinec, Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia; and Brigita Lenarčič, Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia; and Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, SI-1000 Ljubljana, Slovenia


Received: 2013-02-07

Accepted: 2013-04-24

Published Online: 2013-04-27

Published in Print: 2013-09-01


Citation Information: Biological Chemistry, Volume 394, Issue 9, Pages 1163–1179, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2013-0134.

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