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词条 Cathepsin K
释义

  1. Function

  2. Clinical significance

  3. References

  4. Further reading

  5. Additional images

  6. External links

{{Infobox gene}}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 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, called 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 enyzme 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.

References

1. ^{{cite web | title = Entrez Gene: CTSK cathepsin K| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1513| accessdate = }}
2. ^{{cite journal | vauthors = Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T | title = Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone | journal = Biochemical and Biophysical Research Communications| volume = 206 | issue = 1 | pages = 89–96 |date=January 1995 | pmid = 7818555 | doi = 10.1006/bbrc.1995.1013 | url = }}
3. ^{{cite journal | url=http://mct.aacrjournals.org/content/13/12/2898.long | title=Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis | volume=13 | issue=12 | journal=Molecular Cancer Therapeutics| date=23 September 2014 | accessdate=2 October 2016 | author=Duong, Le T., Wesolowski, Gregg A., Leung, Patrick Oballa, Renata and Pickarski, Maureen | pages=2898–909| doi=10.1158/1535-7163.MCT-14-0253 | pmid=25249554 }}
4. ^{{cite web | url=https://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=1513 | title=CTSK cathepsin K [ Homo sapiens (human) ] | publisher=National Center for Biotechnology Information, U.S. National Library of Medicine | work=NCBI Gene | date=4 September 2016 | accessdate=2 October 2016}}
5. ^{{cite journal | title=Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma | journal=PLOS ONE|volume = 9| issue=10 | pages=e111819 | date=30 October 2014 | author=Verbovšek, Urška, Motaln, Helena, Rotter, Ana, Atai, Nadia A., Gruden, Kristina, Van Noorden, Cornelis J.F., Lah, Tamara T.| doi=10.1371/journal.pone.0111819 | pmid=25356585 | pmc=4214761 | bibcode=2014PLoSO...9k1819V}}
6. ^{{cite journal | url=http://ajcp.oxfordjournals.org/content/139/2/151.long | title=A Broad Survey of Cathepsin K Immunoreactivity in Human Neoplasms | volume=139 | issue=2 | journal=American Journal of Clinical Pathology| date=1 February 2013 | accessdate=2 October 2016 | author=Argani, Pedram|display-authors=et al | pages=151–159| doi=10.1309/AJCPDTRTO2Z4UEXD | pmid=23355199 | pmc=3957187 }}
7. ^{{cite web | url=https://www.novusbio.com/primary-antibodies/cathepsin-k | title=Cathepsin K Antibodies | publisher=Novus Biologicals, LLC | work=Novus Biologicals online catalog | date=2016 | accessdate=2 October 2016}}
8. ^{{cite web | url=http://www.abcam.com/cathepsin-k-antibody-ab19027.html | title=Anti-Cathepsin K antibody (ab19027) | publisher=Abcam plc | work=Abcam plc online catalog | date=2016 | accessdate=2 October 2016}}
9. ^{{cite web | url=https://www.antibodies.com/cathepsin-k-antibody-a15026 | title=Anti-Cathepsin K Antibody (A5871) | publisher=Antibodies.com Ltd| work=Antibodies.com online catalog | date=2018 | accessdate=16 January 2018}}
10. ^{{cite journal | title=Cathepsin K inhibitors for osteoporosis and potential off-target effects | journal=Expert Opinion on Investigational Drugs|volume = 18| issue=5 | date=24 April 2009 | author=Brömme, Dieter, Lecaille, Fabien | pages=585–600| doi=10.1517/13543780902832661 | pmid=19388876 | pmc=3110777 }}
11. ^{{cite web | url=http://investors.merck.com/investors/financial-news/press-release-details/2016/Merck-Provides-Update-on-Odanacatib-Development-Program/default.aspx | title=Merck Provides Update on Odanacatib Development Program | publisher=Merck Sharp & Dohme Corp. | website= | date=2 September 2016 | accessdate=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. ^{{Cite journal|last=Ren|first=Zhong-Yuan|last2=Machuca-Gayet|first2=Irma|last3=Domenget|first3=Chantal|last4=Buchet|first4=Rene|last5=Wu|first5=Yuqing|last6=Jurdic|first6=Pierre|last7=Mebarek|first7=Saida|date=2015-07-13|title=Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption|journal=PLOS ONE|volume=10|issue=7|pages=e0132513|doi=10.1371/journal.pone.0132513|pmc=4500499|pmid=26168340|bibcode=2015PLoSO..1032513R}}
15. ^{{Cite web|url=http://www.medivir.se/v5/en/RnD/proj_miv-711.cfm|title=MIV-711 for the treatment of ostheoarthritis|website=www.medivir.se|language=en|access-date=2017-10-06}}
16. ^{{Cite web|url=http://www.medivir.se/v5/images/pdf/2016/OARSI-poster-2016.pdf|title=THE CATHEPSIN K INHIBITOR L-006235 DEMONSTRATES BOTH DISEASE MODIFICATION AND ATTENUATION OF PAIN BEHAVIOUR IN THE IN THE MIA MODEL OF OSTEOARTHRITIS|last=James J. Burston, Luting . Xu, Paul I. Mapp, Urszula Grabowska, Karin Tunblad, Erik Lindström, Victoria Chapman|date=April 2016|website=www.medivir.se|archive-url=|archive-date=|dead-url=|access-date=}}
17. ^{{Cite web|url=http://mb.cision.com/Main/652/2346448/722499.pdf|title=Data monitoring committee gives "Go Ahead" in the MIV-711 osteoarthritis extension study|last=|first=|date=14 September 2017|website=mb.cision.com|archive-url=|archive-date=|dead-url=|access-date=}}

Further reading

{{refbegin | 2}}
  • {{cite journal | vauthors=Motyckova G, Fisher DE |title=Pycnodysostosis: role and regulation of cathepsin K in osteoclast function and human disease. |journal=Current Molecular Medicine|volume=2 |issue= 5 |pages= 407–21 |year= 2003 |pmid= 12125807 |doi=10.2174/1566524023362401 }}
  • {{cite journal | author=Troen BR |title=The regulation of cathepsin K gene expression. |journal=Annals of the New York Academy of Sciences|volume=1068 |issue= 1|pages= 165–72 |year= 2006 |pmid= 16831915 |doi= 10.1196/annals.1346.018 |bibcode=2006NYASA1068..165T }}
  • {{cite journal | vauthors=Del Nery E, Chagas JR, Juliano MA |title=Evaluation of the extent of the binding site in human tissue kallikrein by synthetic substrates with sequences of human kininogen fragments. |journal=The Biochemical Journal|volume=312 |issue= 1|pages= 233–8 |year= 1996 |pmid= 7492318 |doi= | pmc=1136249 |display-authors=etal}}
  • {{cite journal | vauthors=Brömme D, Okamoto K |title=Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. |journal=Biological Chemistry Hoppe-Seyler|volume=376 |issue= 6 |pages= 379–84 |year= 1995 |pmid= 7576232 |doi= 10.1515/bchm3.1995.376.6.379}}
  • {{cite journal | vauthors=Gelb BD, Edelson JG, Desnick RJ |title=Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. |journal=Nature Genetics|volume=10 |issue= 2 |pages= 235–7 |year= 1995 |pmid= 7663521 |doi= 10.1038/ng0695-235 }}
  • {{cite journal | vauthors=Polymeropoulos MH, Ortiz De Luna RI, Ide SE |title=The gene for pycnodysostosis maps to human chromosome 1cen-q21. |journal=Nature Genetics|volume=10 |issue= 2 |pages= 238–9 |year= 1995 |pmid= 7663522 |doi= 10.1038/ng0695-238 |display-authors=etal|url=https://zenodo.org/record/1233385/files/article.pdf }}
  • {{cite journal | vauthors=Shi GP, Chapman HA, Bhairi SM |title=Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. |journal=FEBS Letters|volume=357 |issue= 2 |pages= 129–34 |year= 1995 |pmid= 7805878 |doi=10.1016/0014-5793(94)01349-6 |display-authors=etal}}
  • {{cite journal | vauthors=Inaoka T, Bilbe G, Ishibashi O |title=Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. |journal=Biochemical and Biophysical Research Communications|volume=206 |issue= 1 |pages= 89–96 |year= 1995 |pmid= 7818555 |doi= 10.1006/bbrc.1995.1013 |display-authors=etal}}
  • {{cite journal | vauthors=Velasco G, Ferrando AA, Puente XS |title=Human cathepsin O. Molecular cloning from a breast carcinoma, production of the active enzyme in Escherichia coli, and expression analysis in human tissues. |journal=The Journal of Biological Chemistry|volume=269 |issue= 43 |pages= 27136–42 |year= 1994 |pmid= 7929457 |doi= |display-authors=etal}}
  • {{cite journal | vauthors=Li YP, Alexander M, Wucherpfennig AL |title=Cloning and complete coding sequence of a novel human cathepsin expressed in giant cells of osteoclastomas. |journal=Journal of Bone and Mineral Research|volume=10 |issue= 8 |pages= 1197–202 |year= 1996 |pmid= 8585423 |doi=10.1002/jbmr.5650100809 |display-authors=etal}}
  • {{cite journal | vauthors=Bossard MJ, Tomaszek TA, Thompson SK |title=Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. |journal=Journal of Biological Chemistry|volume=271 |issue= 21 |pages= 12517–24 |year= 1996 |pmid= 8647860 |doi= 10.1074/jbc.271.21.12517|display-authors=etal}}
  • {{cite journal | vauthors=Gelb BD, Shi GP, Chapman HA, Desnick RJ |title=Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. |journal=Science|volume=273 |issue= 5279 |pages= 1236–8 |year= 1996 |pmid= 8703060 |doi=10.1126/science.273.5279.1236 |bibcode=1996Sci...273.1236G }}
  • {{cite journal | vauthors=Johnson MR, Polymeropoulos MH, Vos HL |title=A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. |journal=Genome Research|volume=6 |issue= 11 |pages= 1050–5 |year= 1997 |pmid= 8938428 |doi=10.1101/gr.6.11.1050 |display-authors=etal}}
  • {{cite journal | vauthors=Littlewood-Evans A, Kokubo T, Ishibashi O |title=Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistry. |journal=Bone|volume=20 |issue= 2 |pages= 81–6 |year= 1997 |pmid= 9028530 |doi=10.1016/S8756-3282(96)00351-1 |display-authors=etal}}
  • {{cite journal | vauthors=McGrath ME, Klaus JL, Barnes MG, Brömme D |title=Crystal structure of human cathepsin K complexed with a potent inhibitor. |journal=Nature Structural Biology|volume=4 |issue= 2 |pages= 105–9 |year= 1997 |pmid= 9033587 |doi=10.1038/nsb0297-105 }}
  • {{cite journal | vauthors=Rood JA, Van Horn S, Drake FH |title=Genomic organization and chromosome localization of the human cathepsin K gene (CTSK). |journal=Genomics|volume=41 |issue= 2 |pages= 169–76 |year= 1997 |pmid= 9143491 |doi= 10.1006/geno.1997.4614 |display-authors=etal}}
  • {{cite journal | vauthors=Gelb BD, Shi GP, Heller M |title=Structure and chromosomal assignment of the human cathepsin K gene. |journal=Genomics|volume=41 |issue= 2 |pages= 258–62 |year= 1997 |pmid= 9143502 |doi= 10.1006/geno.1997.4631 |display-authors=etal}}
  • {{cite journal | vauthors=Gomes RA, Juliano L, Chagas JR, Hial V |title=Characterization of kininogenase activity of an acidic proteinase isolated from human kidney. |journal=Canadian Journal of Physiology and Pharmacology|volume=75 |issue= 6 |pages= 757–61 |year= 1997 |pmid= 9276160 |doi=10.1139/cjpp-75-6-757 }}
  • {{cite journal | vauthors=Thompson SK, Halbert SM, Bossard MJ |title=Design of potent and selective human cathepsin K inhibitors that span the active site. |journal=Proceedings of the National Academy of Sciences|volume=94 |issue= 26 |pages= 14249–54 |year= 1998 |pmid= 9405598 |doi=10.1073/pnas.94.26.14249 | pmc=24926 |display-authors=etal}}
  • {{cite journal | vauthors=Gelb BD, Willner JP, Dunn TM |title=Paternal uniparental disomy for chromosome 1 revealed by molecular analysis of a patient with pycnodysostosis. |journal=The American Journal of Human Genetics|pages= 848–54 |year= 1998 |pmid= 9529353 |doi=10.1086/301795 | pmc=1377035 |volume=62 |issue=4|display-authors=etal}}
{{refend}}

Additional images

External links

  • The MEROPS online database for peptidases and their inhibitors: C01.036
  • {{MeshName|Cathepsin+K}}
{{PDB Gallery|geneid=1513}}{{Cysteine proteases}}{{Enzymes}}{{Portal bar|Molecular and Cellular Biology|border=no}}{{Use dmy dates|date=April 2017}}

3 : EC 3.4.22|Peptidase|Cathepsins
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