CTSK

Official Full Name

cathepsin K

Organism

Homo sapiens

GeneID

1513

Background

The protein encoded by this gene is a lysosomal cysteine proteinase involved in bone remodeling and resorption. This protein, which is a member of the peptidase C1 protein family, is predominantly expressed in osteoclasts. However, the encoded protein is also 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. [provided by RefSeq, Apr 2013]

Synonyms

CTSO; PKND; PYCD; CTS02; CTSO1; CTSO2;

Bio Chemical Class

Peptidase

Protein Sequence

MWGLKVLLLPVVSFALYPEEILDTHWELWKKTHRKQYNNKVDEISRRLIWEKNLKYISIHNLEASLGVHTYELAMNHLGDMTSEEVVQKMTGLKVPLSHSRSNDTLYIPEWEGRAPDSVDYRKKGYVTPVKNQGQCGSCWAFSSVGALEGQLKKKTGKLLNLSPQNLVDCVSENDGCGGGYMTNAFQYVQKNRGIDSEDAYPYVGQEESCMYNPTGKAAKCRGYREIPEGNEKALKRAVARVGPVSVAIDASLTSFQFYSKGVYYDESCNSDNLNHAVLAVGYGIQKGNKHWIIKNSWGENWGNKGYILMARNKNNACGIANLASFPKM

Open

Disease

Asthma, Bone cancer, Chronic obstructive pulmonary disease, Chronic pain, Digestive system disease, Hepatic fibrosis/cirrhosis, Low bone mass disorder, Metastatic tumour, Multiple sclerosis, Musculoskeletal system/connective tissue disease, Osteoarthritis, Pain, Postoperative inflammation, Psoriasis, Rheumatoid arthritis

Approved Drug

Clinical Trial Drug

5 +

Discontinued Drug

4 +

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Detailed Information

The CTSK (Cathepsin K) gene encodes a protein belonging to the lysosomal cysteine protease family, primarily involved in bone remodeling and resorption. It is mainly expressed in osteoclasts, which are the primary cells responsible for bone resorption in skeletal metabolism. However, CTSK protein expression is not limited to the skeletal system; it is also found in certain tumor types, particularly breast cancer, where it may contribute to tumor invasiveness. This suggests that CTSK plays a vital role not only in bone metabolism but also in the progression of certain cancers. Additionally, mutations in the CTSK gene are one of the causes of pycnodysostosis, an autosomal recessive disorder characterized by osteosclerosis and dwarfism.

Figure 1 illustrates that cathepsin K expression is induced by TFE3 and TFEB hyperexpression from gene translocation or amplification, or by mTOR pathway activation resulting from TSC1/TSC2 inactivation or mTOR activation mutations. Figure 1. Schematic illustration showing the different mechanisms leading to cathepsin K expression. (Caliò A, et al., 2021)

Functions of CTSK Protein

CTSK protein is a strong endopeptidase capable of cleaving different substrates in acidic conditions. Its most common job is in osteoclasts, where it helps break down collagen and other materials in the bone, leading to bone loss. Besides helping with bone growth, CTSK also plays a part in releasing thyroid hormones. It helps break down thyroglobulin so that the thyroid hormone T4 can be released.

CTSK protein has typical traits of cathepsin proteases. Its active site is found in a V-shaped groove, and it has an important cysteine-histidine pair that helps it function. The enzyme can hold a proline amino acid in the P2 spot because collagen has a lot of proline and hydroxyproline. Inhibiting CTSK can stop bone breakdown without interfering with bone creation, making CTSK an important target for developing drugs that prevent bone loss.

Role of CTSK in Diseases

CTSK is crucial in bone metabolism and is closely linked to the development of various diseases. Its role is most recognized in skeletal diseases, particularly genetic disorders such as pycnodysostosis. These disorders are typically associated with mutations in the CTSK gene, leading to impaired enzyme function and consequently affecting normal bone development. Moreover, CTSK is implicated in the pathogenesis of other conditions such as arthritis, osteoporosis, and certain cancers.

In breast cancer, upregulated CTSK expression may correlate with increased tumor invasiveness and metastatic potential. By degrading the extracellular matrix surrounding tumor cells, CTSK aids in the penetration of tumor cells through the basement membrane into the bloodstream or lymphatic circulation, thereby facilitating metastasis. Consequently, CTSK is regarded as a potential cancer therapeutic target, and inhibiting its activity might help slow cancer progression.

Role of CTSK in the Nervous System

The role of CTSK in the nervous system is gaining attention. Studies have found that while CTSK is crucial for bone function, it is also widely distributed in the brains of adult rats and humans, especially expressed in numerous neurons and glial cells. Studies show that when the CTSK gene is missing, it causes changes in the nervous system of mice. This particularly affects two enzymes, CatB and CatL, in the brain. This suggests that CTSK helps keep the nervous system working properly by controlling these enzymes in the brain.

CTSK absence is linked to several brain-related problems, such as stroke, cerebral aneurysm, and chronic subdural hematoma (CSDH). Research suggests that CTSK helps protect the brain during an acute ischemic stroke (AIS). Mice without CTSK show worse signs like swelling in the brain, damage to the blood-brain barrier, and neural problems after receiving rtPA treatment. Therefore, CTSK may play an essential physiological role in protecting the BBB and reducing brain injury.

Relation of CTSK to Mental Disorders

CTSK's role in mental disorders is gradually being uncovered. Studies suggest a connection between the CTSK gene and the development of schizophrenia, particularly among patients undergoing antipsychotic treatment, where CTSK expression changes significantly. In the brain tissue of schizophrenia patients, CTSK levels are significantly elevated, correlating closely with changes in the encephalin and endorphin systems. Researchers believe that CTSK may play an important role in neuroendocrine regulation.

Role of CTSK in Vascular Diseases

Its role in diseases such as brain tumors has been proven. Research shows that CTSK, along with other cysteine proteases like CatB and CatS, plays a major part in the growth and spread of brain aneurysms. In the later stages of brain aneurysms, the level of CTSK rises a lot, and this is strongly linked to the breakdown of the extracellular matrix. Recent studies show that blocking CTSK activity can stop the growth of brain aneurysms. This offers new possibilities for using CTSK inhibitors in treating blood vessel conditions.

References:

Zaidi M, Troen B, et al. Cathepsin K, osteoclastic resorption, and osteoporosis therapy. J Bone Miner Res. 2001 Oct;16(10):1747-9.
Dai R, Wu Z, et al. Cathepsin K: The Action in and Beyond Bone. Front Cell Dev Biol. 2020 Jun 4;8:433.
Caliò A, Brunelli M, et al. Cathepsin K: A Novel Diagnostic and Predictive Biomarker for Renal Tumors. Cancers (Basel). 2021 May 18;13(10):2441.

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