Cathepsin K

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CTSK
Cathepsin K 1TU6.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CTSK, CTS02, CTSO, CTSO1, CTSO2, PKND, PYCD, cathepsin K
External IDs OMIM: 601105 MGI: 107823 HomoloGene: 68053 GeneCards: CTSK
Targeted by Drug
odanacatib[1]
RNA expression pattern
PBB GE CTSK 202450 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000396

NM_007802

RefSeq (protein)

NP_000387

NP_031828.2
NP_031828

Location (UCSC) Chr 1: 150.8 – 150.81 Mb Chr 3: 95.5 – 95.51 Mb
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.[4][5]

Function[edit]

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 allow 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[edit]

Cathepsin K is also expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness.[6] Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.[7] Cathepsin K has also been found to be over-expressed in glioblastoma.[8]

That the expression of Cathepsin K is characteristic for some cancers and not others has been documented.[9] Cathepsin K antibodies are marketed for research into expression of this enyzme by various cells.[10][11]

Merck had a Cathepsin K inhibitor in Phase 3 clinical trials by the name of odanacatib for an expected indication of osteoporosis. On September 2, 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 in patients receiving odanacatib in Merck's Phase 3 clinical trials.[12][13]

Velcura Therapeutics, Inc. has also developed a highly selective cathepsin K inhibitor named VEL-0230 and has been tested in human, rat, equine clinical trials. [14] [15] [16]

Medvir also has a highly selective cathepsin K inhibitor, named MIV-711, in phase I trial, targeting osteoarthritis, in the specific class of Disease Modifying Osteoarthritis Drugs (DMOADs).[17][18]

References[edit]

  1. ^ "Drugs that physically interact with Cathepsin K view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ "Entrez Gene: CTSK cathepsin K". 
  5. ^ Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (January 1995). "Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone". Biochem. Biophys. Res. Commun. 206 (1): 89–96. doi:10.1006/bbrc.1995.1013. PMID 7818555. 
  6. ^ Duong, Le T. , Wesolowski, Gregg A., Leung, Patrick Oballa, Renata and Pickarski, Maureen (23 September 2014). ""Efficacy of a Cathepsin K Inhibitor in a Preclinical Model for Prevention and Treatment of Breast Cancer Bone Metastasis"". Molecular Cancer Therapeutics; 13(12);. American Association for Cancer Research. pp. 2898–909. Retrieved 2 October 2016. 
  7. ^ ""CTSK cathepsin K [ Homo sapiens (human) ]"". NCBI Gene. National Center for Biotechnology Information, U.S. National Library of Medicine. 4 September 2016. Retrieved 2 October 2016. 
  8. ^ Verbovšek, Urška, Motaln, Helena, Rotter, Ana, Atai, Nadia A., Gruden, Kristina, Van Noorden, Cornelis J.F., Lah, Tamara T. (30 October 2014). ""Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma"". PLOS ONE. LOCKSS. Retrieved 2 October 2016. 
  9. ^ Argani, Pedram; et al. (1 February 2013). ""A Broad Survey of Cathepsin K Immunoreactivity in Human Neoplasms"". American Journal of Clinical Pathology, Volume 139, Issue 2. Oxford Journals. pp. 151–159. Retrieved 2 October 2016. 
  10. ^ ""Cathepsin K Antibodies"". Novus Biologicals online catalog. Novus Biologicals, LLC. 2016. Retrieved 2 October 2016. 
  11. ^ ""Anti-Cathepsin K antibody (ab19027)"". Abcam plc online catalog. Abcam plc. 2016. Retrieved 2 October 2016. 
  12. ^ Brömme, Dieter, Lecaille, Fabien (24 April 2009). ""Cathepsin K inhibitors for osteoporosis and potential off-target effects"". Expert Opinion on Investigational Drugs, Volume 18 2009 - Issue 5. Taylor & Francis Online. pp. 585–600. Retrieved 2 October 2016. 
  13. ^ ""Merck Provides Update on Odanacatib Development Program"". Merck Sharp & Dohme Corp. 2 September 2016. Retrieved 1 October 2016. 
  14. ^ http://www.prnewswire.com/news-releases/velcura-therapeutics-inc-to-begin-clinical-trials-in-rheumatoid-arthritis-patients-60778142.html
  15. ^ 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.
  16. ^ 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.
  17. ^ "Osteoarthritis - MIV-711 – a cathepsin K inhibitor". www.medivir.se. Retrieved 2017-02-16. 
  18. ^ 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). doi:10.1371/journal.pone.0132513. ISSN 1932-6203. PMC 4500499Freely accessible. PMID 26168340. 

Further reading[edit]

Additional images[edit]

External links[edit]