Relationship between cathepsin K and extracellular matrix dynamics: a comprehensive review

Area of Science:

• Biochemistry
• Pathology
• Pharmacology

Background:

• Cathepsin K (CTSK) is primarily known for its role in bone resorption.
• Emerging evidence highlights CTSK's broader functions in extracellular matrix (ECM) remodeling and cellular processes like epithelial-mesenchymal transition (EMT).
• Understanding these pleiotropic roles is crucial for exploring new therapeutic avenues.

Purpose of the Study:

• To systematically review the diverse functions of Cathepsin K (CTSK) beyond bone resorption.
• To elucidate CTSK's role in regulating ECM dynamics and EMT in various pathological conditions.
• To evaluate the therapeutic potential and risks associated with CTSK inhibitors.

Main Methods:

• A comprehensive literature analysis was performed to synthesize information on CTSK's molecular architecture and signaling pathways (e.g., RANKL-RANK, NF-κB).
• Evidence was stratified across five key pathological domains: oncology, cardiovascular diseases, pulmonary disorders, orthopedic conditions, and metabolic diseases.
• The development and associated risks of CTSK inhibitors were evaluated.

Main Results:

• CTSK is a versatile protease involved in ECM remodeling, facilitating metastasis in various cancers by degrading matrix barriers and promoting EMT.
• In cardiovascular and pulmonary diseases, CTSK has a dual role, contributing to plaque instability and fibrosis but offering protection in ischemic remodeling.
• Upregulated CTSK in metabolic disorders (T2DM, obesity) leads to pathological collagen degradation, while in orthopedic diseases, it drives bone matrix degradation and impairs tissue repair.
• CTSK inhibitors show therapeutic promise but carry risks such as off-target effects and increased stroke risk.

Conclusions:

• CTSK acts as a central regulator of systemic ECM homeostasis, making it a significant therapeutic target.
• Developing highly selective CTSK inhibitors is essential for precise therapeutic regulation.
• Future strategies must balance treatment efficacy with patient safety, addressing potential adverse effects.