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Cathepsin K

From Wikipedia, the free encyclopedia
CTSK
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCTSK, CTS02, CTSO, CTSO1, CTSO2, PKND, PYCD, cathepsin K
External IDsOMIM: 601105; MGI: 107823; HomoloGene: 68053; GeneCards: CTSK; OMA:CTSK - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000396

NM_007802

RefSeq (protein)

NP_000387

NP_031828

Location (UCSC)Chr 1: 150.79 – 150.81 MbChr 3: 95.41 – 95.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Cathepsin K, abbreviated CTSK, is an enzyme that in humans is encoded by the CTSK gene.[5][6]

Function

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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

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Cathepsin K is expressed in a significant fraction of human breast cancers, where it could contribute to tumor invasiveness.[7] Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature.[8] Cathepsin K has also been found to be over-expressed in glioblastoma.[9]

That the expression of cathepsin K is characteristic for some cancers and not others has been documented.[10] Cathepsin K antibodies are marketed for research into expression of this enzyme by various cells.[11][12][13]

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.[14][15] Other cathepsin K inhibitors are in various stages of development.[16][17][18] Medivir has a cathepsin K inhibitor, MIV-711 (L-006235[19][20][21]), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000143387Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028111Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: CTSK cathepsin K".
  6. ^ 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". Biochemical and Biophysical Research Communications. 206 (1): 89–96. doi:10.1006/bbrc.1995.1013. PMID 7818555.
  7. ^ Duong LT, Wesolowski GA, Leung P, Oballa R, Pickarski M (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): 2898–909. doi:10.1158/1535-7163.MCT-14-0253. PMID 25249554. Retrieved 2 October 2016.
  8. ^ "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.
  9. ^ Verbovšek U, Motaln H, Rotter A, Atai NA, Gruden K, Van Noorden CJ, Lah TT (30 October 2014). "Expression Analysis of All Protease Genes Reveals Cathepsin K to Be Overexpressed in Glioblastoma". PLOS ONE. 9 (10): e111819. Bibcode:2014PLoSO...9k1819V. doi:10.1371/journal.pone.0111819. PMC 4214761. PMID 25356585.
  10. ^ Argani, Pedram; et al. (1 February 2013). "A Broad Survey of Cathepsin K Immunoreactivity in Human Neoplasms". American Journal of Clinical Pathology. 139 (2): 151–159. doi:10.1309/AJCPDTRTO2Z4UEXD. PMC 3957187. PMID 23355199.
  11. ^ "Cathepsin K Antibodies". Novus Biologicals online catalog. Novus Biologicals, LLC. 2016. Retrieved 2 October 2016.
  12. ^ "Anti-Cathepsin K antibody (ab19027)". Abcam plc online catalog. Abcam plc. 2016. Retrieved 2 October 2016.
  13. ^ "Anti-Cathepsin K Antibody (A5871)". Antibodies.com online catalog. Antibodies.com Ltd. 2018. Retrieved 16 January 2018.
  14. ^ Brömme, Dieter; Lecaille, Fabien (24 April 2009). "Cathepsin K inhibitors for osteoporosis and potential off-target effects". Expert Opinion on Investigational Drugs. 18 (5): 585–600. doi:10.1517/13543780902832661. PMC 3110777. PMID 19388876.
  15. ^ "Merck Provides Update on Odanacatib Development Program". Merck Sharp & Dohme Corp. 2 September 2016. Retrieved 1 October 2016.
  16. ^ 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.
  17. ^ 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.
  18. ^ Ren, Zhong-Yuan; Machuca-Gayet, Irma; Domenget, Chantal; Buchet, Rene; Wu, Yuqing; Jurdic, Pierre; Mebarek, Saida (13 July 2015). "Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption". PLOS ONE. 10 (7): e0132513. Bibcode:2015PLoSO..1032513R. doi:10.1371/journal.pone.0132513. PMC 4500499. PMID 26168340.
  19. ^ "MIV-711 for the treatment of ostheoarthritis". www.medivir.se. Archived from the original on 6 October 2017. Retrieved 6 October 2017.
  20. ^ Burston JJ, Xu L, Mapp PI, Grabowska U, Tunblad K, Lindström E, Chapman V (April 2016). "The Cathepsin K Inhibitor L-006235 Demonstrates Both Disease Modification and Attenuation of Pain Behaviour in the in the [sic] Mia Model of Osteoarthritis" (PDF). www.medivir.se. Archived from the original (PDF) on 6 October 2017. Retrieved 6 October 2017.
  21. ^ "Data monitoring committee gives "Go Ahead" in the MIV-711 osteoarthritis extension study" (PDF). mb.cision.com. 14 September 2017.

Further reading

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Additional images

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