Cathepsin K Explained

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.^{[1] [2]}

Function

The protein encoded by this gene is a cysteine cathepsin, a lysosomal cysteine protease involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is expressed predominantly in osteoclasts.

Cathepsin K is a protease, which is defined by its high specificity for kinins, that is involved in bone resorption. The enzyme's ability to catabolize elastin, collagen, and gelatin allows it to break down bone and cartilage. This catabolic activity is also partially responsible for the loss of lung elasticity and recoil in emphysema. Cathepsin K inhibitors show great potential in the treatment of osteoporosis. Cathepsin K is degraded by Cathepsin S, in a process referred to as Controlled Cathepsin Cannibalism.

Cathepsin K expression is stimulated by inflammatory cytokines that are released after tissue injury.

Clinical significance

Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness.^[3] Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.^[4] Cathepsin K has also been found to be over-expressed in glioblastoma.^[5]

That the expression of cathepsin K is characteristic for some cancers and not others has been documented.^[6] Cathepsin K antibodies are marketed for research into expression of this enzyme by various cells.^{[7] [8] [9]}

Merck had a cathepsin K inhibitor, odanacatib, in Phase III clinical trials for osteoporosis. In September, 2016, Merck announced they were discontinuing development of odanacatib after their own assessment of adverse events and an independent assessment showed increased risk of stroke.^{[10] [11]} Other cathepsin K inhibitors are in various stages of development.^{[12] [13] [14]} Medivir has a cathepsin K inhibitor, MIV-711 (L-006235^{[15] [16] [17]}), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.

Further reading

• Motyckova G, Fisher DE . Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. . Current Molecular Medicine. 2 . 5 . 407–21 . 2003 . 12125807 . 10.2174/1566524023362401 .
• Troen BR . The regulation of cathepsin K gene expression. . Annals of the New York Academy of Sciences. 1068 . 1. 165–72 . 2006 . 16831915 . 10.1196/annals.1346.018 . 2006NYASA1068..165T . 8117602 . free .
• Del Nery E, Chagas JR, Juliano MA . Evaluation of the extent of the binding site in human tissue kallikrein by synthetic substrates with sequences of human kininogen fragments. . The Biochemical Journal. 312 . 1. 233–8 . 1996 . 7492318 . 10.1042/bj3120233. 1136249 . etal.
• Brömme D, Okamoto K . Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. . Biological Chemistry Hoppe-Seyler. 376 . 6 . 379–84 . 1995 . 7576232 . 10.1515/bchm3.1995.376.6.379.
• Gelb BD, Edelson JG, Desnick RJ . Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. . Nature Genetics. 10 . 2 . 235–7 . 1995 . 7663521 . 10.1038/ng0695-235 . 24297764 .
• Polymeropoulos MH, Ortiz De Luna RI, Ide SE . The gene for pycnodysostosis maps to human chromosome 1cen-q21. . Nature Genetics. 10 . 2 . 238–9 . 1995 . 7663522 . 10.1038/ng0695-238 . 11723845 . etal.
• Shi GP, Chapman HA, Bhairi SM . Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. . FEBS Letters. 357 . 2 . 129–34 . 1995 . 7805878 . 10.1016/0014-5793(94)01349-6 . 28099876 . etal. free .
• Inaoka T, Bilbe G, Ishibashi O . Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. . Biochemical and Biophysical Research Communications. 206 . 1 . 89–96 . 1995 . 7818555 . 10.1006/bbrc.1995.1013 . etal.
• Velasco G, Ferrando AA, Puente XS . Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues. . The Journal of Biological Chemistry. 269 . 43 . 27136–42 . 1994 . 10.1016/S0021-9258(18)47135-9 . 7929457 . etal. free .
• Li YP, Alexander M, Wucherpfennig AL . Cloning and complete coding sequence of a novel human cathepsin expressed in giant cells of osteoclastomas. . Journal of Bone and Mineral Research. 10 . 8 . 1197–202 . 1996 . 8585423 . 10.1002/jbmr.5650100809 . 41832979 . etal.
• Bossard MJ, Tomaszek TA, Thompson SK . Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. . Journal of Biological Chemistry. 271 . 21 . 12517–24 . 1996 . 8647860 . 10.1074/jbc.271.21.12517. etal. free .
• Gelb BD, Shi GP, Chapman HA, Desnick RJ . Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. . Science. 273 . 5279 . 1236–8 . 1996 . 8703060 . 10.1126/science.273.5279.1236 . 1996Sci...273.1236G . 7188076 .
• Johnson MR, Polymeropoulos MH, Vos HL . A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. . Genome Research. 6 . 11 . 1050–5 . 1997 . 8938428 . 10.1101/gr.6.11.1050 . etal. free .
• Littlewood-Evans A, Kokubo T, Ishibashi O . Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry. . Bone. 20 . 2 . 81–6 . 1997 . 9028530 . 10.1016/S8756-3282(96)00351-1 . etal.
• McGrath ME, Klaus JL, Barnes MG, Brömme D . Crystal structure of human cathepsin K complexed with a potent inhibitor. . Nature Structural Biology. 4 . 2 . 105–9 . 1997 . 9033587 . 10.1038/nsb0297-105 . 22175354 .
• Rood JA, Van Horn S, Drake FH . Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). . Genomics. 41 . 2 . 169–76 . 1997 . 9143491 . 10.1006/geno.1997.4614 . etal.
• Gelb BD, Shi GP, Heller M . Structure and chromosomal assignment of the human cathepsin K gene. . Genomics. 41 . 2 . 258–62 . 1997 . 9143502 . 10.1006/geno.1997.4631 . etal.
• Gomes RA, Juliano L, Chagas JR, Hial V . Characterization of kininogenase activity of an acidic proteinase isolated from human kidney. . Canadian Journal of Physiology and Pharmacology. 75 . 6 . 757–61 . 1997 . 9276160 . 10.1139/cjpp-75-6-757 .
• Thompson SK, Halbert SM, Bossard MJ . Design of potent and selective human cathepsin K inhibitors that span the active site. . Proceedings of the National Academy of Sciences. 94 . 26 . 14249–54 . 1998 . 9405598 . 10.1073/pnas.94.26.14249 . 24926 . etal. free .
• Gelb BD, Willner JP, Dunn TM . Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. . The American Journal of Human Genetics. 848–54 . 1998 . 9529353 . 10.1086/301795 . 1377035 . 62 . 4. etal.

External links

• The MEROPS online database for peptidases and their inhibitors: C01.036

Notes and References

1. Web site: Entrez Gene: CTSK cathepsin K.
2. Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T . Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone . Biochemical and Biophysical Research Communications. 206 . 1 . 89–96 . January 1995 . 7818555 . 10.1006/bbrc.1995.1013 .
3. Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis . 13 . 12 . Molecular Cancer Therapeutics. 23 September 2014 . 2 October 2016 . Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M . 2898–909. 10.1158/1535-7163.MCT-14-0253 . 25249554 . free .
4. Web site: CTSK cathepsin K [Homo sapiens (human) ] ]. National Center for Biotechnology Information, U.S. National Library of Medicine . NCBI Gene . 4 September 2016 . 2 October 2016.
5. Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma . PLOS ONE. 9. 10 . e111819 . 30 October 2014 . Verbovšek U, Motaln H, Rotter A, Atai NA, Gruden K, Van Noorden CJ, Lah TT. 10.1371/journal.pone.0111819 . 25356585 . 4214761 . 2014PLoSO...9k1819V. free.
6. 139 . 2 . American Journal of Clinical Pathology. 1 February 2013 . Argani, Pedram. et al . 151–159. 10.1309/AJCPDTRTO2Z4UEXD . 23355199 . 3957187 .
7. Web site: Cathepsin K Antibodies . Novus Biologicals, LLC . Novus Biologicals online catalog . 2016 . 2 October 2016.
8. Web site: Anti-Cathepsin K antibody (ab19027) . Abcam plc . Abcam plc online catalog . 2016 . 2 October 2016.
9. Web site: Anti-Cathepsin K Antibody (A5871) . Antibodies.com Ltd. Antibodies.com online catalog . 2018 . 16 January 2018.
10. Cathepsin K inhibitors for osteoporosis and potential off-target effects . Expert Opinion on Investigational Drugs. 18. 5 . 24 April 2009 . Brömme . Dieter . Lecaille . Fabien . Dieter Brömme . 585–600. 10.1517/13543780902832661 . 19388876 . 3110777 .
11. Web site: Merck Provides Update on Odanacatib Development Program . Merck Sharp & Dohme Corp. . 2 September 2016 . 1 October 2016.
12. Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, Nishikawa K, Latz E, Golenbock DT, Aoki K, Ohya K, Imai Y, Morishita Y, Miyazono K, Kato S, Saftig P, Takayanagi H,. (2008). Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science, 319(5863), 624-627.
13. Hussein, H., Ishihara, A., Menendez, M., & Bertone, A. (2014). Pharmacokinetics and bone resorption evaluation of a novel Cathepsin K inhibitor (VEL‐0230) in healthy adult horses. Journal of veterinary pharmacology and therapeutics.
14. Ren. Zhong-Yuan. Machuca-Gayet. Irma. Domenget. Chantal. Buchet. Rene. Wu. Yuqing. Jurdic. Pierre. Mebarek. Saida. 2015-07-13. Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption. PLOS ONE. 10. 7. e0132513. 10.1371/journal.pone.0132513. 4500499. 26168340. 2015PLoSO..1032513R. free.
15. Web site: MIV-711 for the treatment of ostheoarthritis. www.medivir.se. en. 2017-10-06. https://web.archive.org/web/20171006212309/http://www.medivir.se/v5/en/RnD/proj_miv-711.cfm. 6 October 2017. dead.
16. Web site: The Cathepsin K Inhibitor L-006235 Demonstrates Both Disease Modification and Attenuation of Pain Behaviour }} Mia Model of Osteoarthritis]. Burston JJ, Xu L, Mapp PI, Grabowska U, Tunblad K, Lindström E, Chapman V . April 2016. www.medivir.se. 6 October 2017. https://web.archive.org/web/20171006212330/http://www.medivir.se/v5/images/pdf/2016/OARSI-poster-2016.pdf. 6 October 2017.
17. Web site: Data monitoring committee gives "Go Ahead" in the MIV-711 osteoarthritis extension study. 14 September 2017. mb.cision.com.