Abstract
Cathepsin K (CTSK), a cysteine protease predominantly seen in osteoclasts, degrades protein present in the organic matrix of bone inducing bone resorption. Based on the accumulating evidences, CTSK has an established role in osteoclast mediated bone resorption, progression of cancer invasion, migration and extracellular matrix degradation through activating several pathways, which vary from other classes of cysteine proteinases such as Cathepsin B & L. Studies in the past have shown that CTSK is a key protease in breast cancer-induced bone metastases which are found highly expressed in human breast and prostate carcinomas. However, the involvement of CTSK in breast and prostate cancer development remains unclear. Bone is a key site of breast and prostate cancer metastasis and most patients with advanced disease encounter complications from incurable bone lesions. Therefore, CTSK can be viewed as an alternative target for treating patients with metastatic bone disease. This review discusses the molecular insights into CTSK and its specific targets in mediating breast cancer skeletal metastasis, so as to find the novelty of cathepsin K therapeutic target for the treatment of patients with osteolytic bone metastases.
Highlights
A skeletal lesion of metastatic bone disease adds significant extent to morbidity and mortality in patients with breast cancer
We provided an insight into the role of lysosomal protease Cathepsin K (CTSK) in bone metastasis, with a focus on extracellular matrix (ECM) degradation, proteolytic cascade activation, and tumor progression [Figure1]
Numerous researches have shown the contribution of CTSK towards tumor progression in skeletal tissue [116,117]
Summary
A skeletal lesion of metastatic bone disease adds significant extent to morbidity and mortality in patients with breast cancer. CTSK degrades the ECM components, including osteonectin, vascular endothelial growth factor (VEGF), adiponectin, osteopontin, and stromal cell derived factor 1 (SDF1) in addition to cleavage of Type I & II collagen This cleavage results in alteration of signaling within the niche to loosen the anchorage of stem cells to the extracellular matrix (ECM) [32]. CTSK plays a crucial role in ECM degradation and extracellular matrix remodeling, which makes a significant contribution to the tumor metastasis It is well documented by many experimental and clinical observations, which highlight, that the expression levels of this proteinase are up regulated in bone diseases associated bone resorption including cancer induced osteolysis (16-17) and that the administration of selective CTSK inhibitor prevent cancer induced bone resorption and bone metastasis in human trial and animal model studies[40,41,42,43,44,45,46]
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