Cathepsin K (CTSK) in Inflammatory and Immune-Mediated Diseases

INTRODUCTION: Cathepsin K (CTSK) is a lysosomal cysteine protease of the papain superfamily. The enzyme plays a key role in bone homeostasis. Immune cells such as dendritic cells, macrophages, and T cells all express CTSK. It modulates inflammation and immunity through NF-κB, TLR, and the RANKL/RANK/OPG axis. Overexpression or underexpression of CTSK appears in rheumatoid arthritis, periodontitis, tumors, and inflammatory bowel disease. Targeted inhibitors and monoclonal antibodies against CTSK are now emerging therapies. METHODS: Systematic literature search and critical review of experimental and clinical studies examining CTSK expression, genetic modulation, and targeted inhibition in inflammatory and immune-mediated disease models. RESULTS: Elevated CTSK correlates with disease activity and bone destruction; its inhibition reduces inflammatory cytokines, immune-cell infiltration, and extracellular-matrix degradation. Small-molecule inhibitors (odanacatib, MIV-711, ONO-5334) and biologics attenuate pathology in arthritis, periodontitis, and atherosclerosis. DISCUSSION: CTSK is a promising diagnostic biomarker and therapeutic target, yet its promise hinges on inhibitors that act only where needed, sparing other tissues. Next steps must therefore craft more selective allosteric compounds and test ways to confine them to diseased sites.