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Gene Review

Ctsk  -  cathepsin K

Mus musculus

Synonyms: AI323530, Cat K, Cathepsin K, MMS10-Q, Ms10q, ...
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Disease relevance of Ctsk


High impact information on Ctsk

  • Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the pycnodysostosis region [5].
  • These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis [5].
  • Transient transfection experiments revealed that overexpression of JDP2 leads to activation of both tartrate-resistant acid phosphatase (TRAP) and cathepsin K gene promoters in RAW264.7 cells [6].
  • The typical multilayered appearance of extracellularly stored thyroglobulin was retained in cathepsin K(-/-) mice only [7].
  • Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production [8].

Chemical compound and disease context of Ctsk


Biological context of Ctsk

  • Some features of the phenotype of Ctsk knockout mice, however, suggest the presence of mechanisms by which Ctsk-deficient mice compensate for the lack of cathepsin K [1].
  • To study these mechanisms in detail, we generated Ctsk-deficient (Ctsk-/-) mice and analyzed them at the age of 2, 7, and 12 months using peripheral quantitative computed tomography, histomorphometry, resorption marker measurements, osteoclast and osteoblast differentiation cultures, and gene expression analyses [1].
  • This places Ctsk approximately 4.5 kb downstream of Arnt on mouse chromosome 3 at locus 47.9 [12].
  • Detailed sequence analysis of 1.7 kb of Ctsk promoter revealed several putative binding sites for transcription factors and two stretches of 280-320 bp which were > 70% homologous with the human cathepsin K promoter [12].
  • The sizes of the coding exons 2-7 as well as the pattern of intron sizes are conserved between the human and mouse cathepsin K genes [12].

Anatomical context of Ctsk

  • The number of osteoclasts in trabecular bone was significantly increased in Ctsk-/- mice compared to controls, as was the number of osteoclast precursors in bone marrow [1].
  • Pulmonary macrophages and fibroblasts were identified as Cat K overproducing cells in the lung of silicotic mice [2].
  • Cathepsin-K-deficient mice survive and are fertile, but display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space [3].
  • Cathepsin-K-deficient osteoclasts manifested a modified ultrastructural appearance: their resorptive surface was poorly defined with a broad demineralized matrix fringe containing undigested fine collagen fibrils; their ruffled borders lacked crystal-like inclusions, and they were devoid of collagen-fibril-containing cytoplasmic vacuoles [3].
  • In areas of cartilage degeneration, both chondrocytes and cells of hypertrophic synovia were positive for cathepsin K [4].

Associations of Ctsk with chemical compounds

  • Epoxy succinate peptide derivatives, CLIK-066, 088, 112, 121, 148, 181, 185 and 187, are typical specific inhibitors for cathepsin L. Aldehyde derivatives CLIK-060 and CLIK-164 showed specific inhibition against cathepsin S and cathepsin K, respectively [13].
  • RAW.CLM-1 cells fail to multinucleate and do not up-regulate calcitonin receptor, but they express tartrate-resistant acid phosphatase, cathepsin K, and beta(3) integrin, suggesting that osteoclastogenesis is blocked at a late-intermediate stage [14].
  • The sequence of cathepsin K expression was linked to osteoclast differentiation in vivo and in vitro by a tartrate-resistant acid phosphatase-anticathepsin K dual immunostaining technique [15].
  • In vitro, recombinant cathepsin K liberated thyroxine from thyroglobulin by limited proteolysis at neutral pH [16].
  • Calvarial Osteoclasts Express a Higher Level of Tartrate-Resistant Acid Phosphatase than Long Bone Osteoclasts and Activation Does not Depend on Cathepsin K or L Activity [17].
  • These studies suggest that cathepsin K interaction with type I collagen is required for 1) the release of cryptic Arg-Gly-Asp motifs during the initial attachment of osteoclasts and 2) termination of resorption via the creation of autocrine signals originating from type I collagen degradation [18].

Regulatory relationships of Ctsk


Other interactions of Ctsk

  • Synthesis and secretion of CAL were up-regulated by 1alpha,25-(OH)2D3, but neither those of CAK, dominant relative to CAL, nor CAB, barely detectable, levels changed in the experiments [22].
  • CONCLUSION: Altogether, these data suggest that while Cat K may contribute to control lung fibrosis, TGF-beta appears to limit its overexpression in response to silica particles [2].
  • Z-Gly-Pro-Arg-MbetaNA is efficiently hydrolyzed by cathepsin K but only poorly by cathepsins L, S, and B. On the contrary, the intracellular hydrolysis of the cathepsin B-specific substrate, Z-Arg-Arg-MbetaNA, was prevented by both types of inhibitors [9].
  • RESULTS: The analyses of the cathepsin-deficient bone explants showed that, in addition to cathepsin K, calvarial osteoclasts use other cysteine proteinases to degrade bone matrix [23].
  • In vitro modified low density lipoprotein (LDL) uptake assays, using bone marrow derived macrophages preincubated with caveolae and scavenger receptor inhibitors, confirmed the importance of caveolins and CD36 in increasing modified LDL uptake in the absence of cathepsin K [24].

Analytical, diagnostic and therapeutic context of Ctsk


  1. Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Kiviranta, R., Morko, J., Alatalo, S.L., NicAmhlaoibh, R., Risteli, J., Laitala-Leinonen, T., Vuorio, E. Bone (2005) [Pubmed]
  2. Overexpression of cathepsin K during silica-induced lung fibrosis and control by TGF-beta. van den Brûle, S., Misson, P., Bühling, F., Lison, D., Huaux, F. Respir. Res. (2005) [Pubmed]
  3. Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Saftig, P., Hunziker, E., Wehmeyer, O., Jones, S., Boyde, A., Rommerskirch, W., Moritz, J.D., Schu, P., von Figura, K. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Spontaneous development of synovitis and cartilage degeneration in transgenic mice overexpressing cathepsin K. Morko, J., Kiviranta, R., Joronen, K., Säämänen, A.M., Vuorio, E., Salminen-Mankonen, H. Arthritis Rheum. (2005) [Pubmed]
  5. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Gelb, B.D., Shi, G.P., Chapman, H.A., Desnick, R.J. Science (1996) [Pubmed]
  6. Jun dimerization protein 2 (JDP2), a member of the AP-1 family of transcription factor, mediates osteoclast differentiation induced by RANKL. Kawaida, R., Ohtsuka, T., Okutsu, J., Takahashi, T., Kadono, Y., Oda, H., Hikita, A., Nakamura, K., Tanaka, S., Furukawa, H. J. Exp. Med. (2003) [Pubmed]
  7. Thyroid functions of mouse cathepsins B, K, and L. Friedrichs, B., Tepel, C., Reinheckel, T., Deussing, J., von Figura, K., Herzog, V., Peters, C., Saftig, P., Brix, K. J. Clin. Invest. (2003) [Pubmed]
  8. IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion. Lubberts, E., Joosten, L.A., Chabaud, M., van Den Bersselaar, L., Oppers, B., Coenen-De Roo, C.J., Richards, C.D., Miossec, P., van Den Berg, W.B. J. Clin. Invest. (2000) [Pubmed]
  9. Localization of rat cathepsin K in osteoclasts and resorption pits: inhibition of bone resorption and cathepsin K-activity by peptidyl vinyl sulfones. Xia, L., Kilb, J., Wex, H., Li, Z., Lipyansky, A., Breuil, V., Stein, L., Palmer, J.T., Dempster, D.W., Brömme, D. Biol. Chem. (1999) [Pubmed]
  10. Peptidic 1-cyanopyrrolidines: synthesis and SAR of a series of potent, selective cathepsin inhibitors. Rydzewski, R.M., Bryant, C., Oballa, R., Wesolowski, G., Rodan, S.B., Bass, K.E., Wong, D.H. Bioorg. Med. Chem. (2002) [Pubmed]
  11. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. Stroup, G.B., Lark, M.W., Veber, D.F., Bhattacharyya, A., Blake, S., Dare, L.C., Erhard, K.F., Hoffman, S.J., James, I.E., Marquis, R.W., Ru, Y., Vasko-Moser, J.A., Smith, B.R., Tomaszek, T., Gowen, M. J. Bone Miner. Res. (2001) [Pubmed]
  12. Complete genomic structure of the mouse cathepsin K gene (Ctsk) and its localization next to the Arnt gene on mouse chromosome 3. Rantakokko, J., Kiviranta, R., Eerola, R., Aro, H.T., Vuorio, E. Matrix Biol. (1999) [Pubmed]
  13. Study of the functional share of lysosomal cathepsins by the development of specific inhibitors. Katunuma, N., Matsui, A., Kakegawa, T., Murata, E., Asao, T., Ohba, Y. Adv. Enzyme Regul. (1999) [Pubmed]
  14. CMRF-35-like molecule-1, a novel mouse myeloid receptor, can inhibit osteoclast formation. Chung, D.H., Humphrey, M.B., Nakamura, M.C., Ginzinger, D.G., Seaman, W.E., Daws, M.R. J. Immunol. (2003) [Pubmed]
  15. Characterization of mouse cathepsin K gene, the gene promoter, and the gene expression. Li, Y.P., Chen, W. J. Bone Miner. Res. (1999) [Pubmed]
  16. Cathepsin K in thyroid epithelial cells: sequence, localization and possible function in extracellular proteolysis of thyroglobulin. Tepel, C., Brömme, D., Herzog, V., Brix, K. J. Cell. Sci. (2000) [Pubmed]
  17. Calvarial Osteoclasts Express a Higher Level of Tartrate-Resistant Acid Phosphatase than Long Bone Osteoclasts and Activation Does not Depend on Cathepsin K or L Activity. Perez-Amodio, S., Jansen, D.C., Schoenmaker, T., Vogels, I.M., Reinheckel, T., Hayman, A.R., Cox, T.M., Saftig, P., Beertsen, W., Everts, V. Calcif. Tissue Int. (2006) [Pubmed]
  18. Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption. Wilson, S.R., Peters, C., Saftig, P., Brömme, D. J. Biol. Chem. (2009) [Pubmed]
  19. Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. Matsumoto, M., Kogawa, M., Wada, S., Takayanagi, H., Tsujimoto, M., Katayama, S., Hisatake, K., Nogi, Y. J. Biol. Chem. (2004) [Pubmed]
  20. Interferon-gamma down-regulates gene expression of cathepsin K in osteoclasts and inhibits osteoclast formation. Kamolmatyakul, S., Chen, W., Li, Y.P. J. Dent. Res. (2001) [Pubmed]
  21. Comparison in localization between cystatin C and cathepsin K in osteoclasts and other cells in mouse tibia epiphysis by immunolight and immunoelectron microscopy. Yamaza, T., Tsuji, Y., Goto, T., Kido, M.A., Nishijima, K., Moroi, R., Akamine, A., Tanaka, T. Bone (2001) [Pubmed]
  22. Regulation of collagenolytic protease secretion through c-Src in osteoclasts. Furuyama, N., Fujisawa, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  23. Osteoclastic bone degradation and the role of different cysteine proteinases and matrix metalloproteinases: differences between calvaria and long bone. Everts, V., Korper, W., Hoeben, K.A., Jansen, I.D., Bromme, D., Cleutjens, K.B., Heeneman, S., Peters, C., Reinheckel, T., Saftig, P., Beertsen, W. J. Bone Miner. Res. (2006) [Pubmed]
  24. Gene profiling of cathepsin K deficiency in atherogenesis: profibrotic but lipogenic. Lutgens, S., Kisters, N., Lutgens, E., van Haaften, R., Evelo, C., de Winther, M., Saftig, P., Daemen, M., Heeneman, S., Cleutjens, K. J. Pathol. (2006) [Pubmed]
  25. Cathepsin K mRNA detection is restricted to osteoclasts during fetal mouse development. Dodds, R.A., Connor, J.R., Drake, F., Feild, J., Gowen, M. J. Bone Miner. Res. (1998) [Pubmed]
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