Cathepsin K

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. Mutations in this gene are the cause of pycnodysostosis, an autosomal recessive disease characterized by osteosclerosis and short stature. Cathepsin K has also been found to be over-expressed in glioblastoma.

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

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. Other cathepsin K inhibitors are in various stages of development. Medivir has a cathepsin K inhibitor, MIV-711 (L-006235), in Phase IIa clinical trial, as a disease modifying osteoarthritis drug, as of October 2017.

References

Additional images

Image:Osteoclast1.jpg|Osteoclast

References

1. "Entrez Gene: CTSK cathepsin K".
2. (January 1995). "Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone". Biochemical and Biophysical Research Communications.
3. (December 2014). "Efficacy of a cathepsin K inhibitor in a preclinical model for prevention and treatment of breast cancer bone metastasis". Molecular Cancer Therapeutics.
4. (4 September 2016). "CTSK cathepsin K [ Homo sapiens (human) ]". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. (30 October 2014). "Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma". PLOS ONE.
6. (February 2013). "A broad survey of cathepsin K immunoreactivity in human neoplasms". American Journal of Clinical Pathology.
7. (2016). "Cathepsin K Antibodies". Novus Biologicals, LLC.
8. (2016). "Anti-Cathepsin K antibody (ab19027)". Abcam plc.
9. (2018). "Anti-Cathepsin K Antibody (A5871)". Antibodies.com Ltd.
10. (May 2009). "Cathepsin K inhibitors for osteoporosis and potential off-target effects". Expert Opinion on Investigational Drugs.
11. (2 September 2016). "Merck Provides Update on Odanacatib Development Program". Merck Sharp & Dohme Corp..
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. (2015-07-13). "Azanitrile Cathepsin K Inhibitors: Effects on Cell Toxicity, Osteoblast-Induced Mineralization and Osteoclast-Mediated Bone Resorption". PLOS ONE.
15. "MIV-711 for the treatment of ostheoarthritis".
16. (April 2016). "The Cathepsin K Inhibitor L-006235 Demonstrates Both Disease Modification and Attenuation of Pain Behaviour {{as written".
17. (14 September 2017). "Data monitoring committee gives "Go Ahead" in the MIV-711 osteoarthritis extension study".