Cathepsin K: a unique collagenolytic cysteine peptidase

Abstract

Cathepsin K has emerged as a promising target for the treatment of osteoporosis in recent years. Initially identified as a papain-like cysteine peptidase expressed in high levels in osteoclasts, the important role of this enzyme in bone metabolism was highlighted by the finding that mutations in the CTSK gene cause the rare recessive disorder pycnodysostosis, which is characterized by severe bone anomalies. At the molecular level, the physiological role of cathepsin K is reflected by its unique cleavage pattern of type I collagen molecules, which is fundamentally different from that of other endogenous collagenases. Several cathepsin K inhibitors have been developed to reduce the excessive bone matrix degradation associated with osteoporosis, with the frontrunner odanacatib about to successfully conclude Phase 3 clinical trials. Apart from osteoclasts, cathepsin K is expressed in different cell types throughout the body and is involved in processes of adipogenesis, thyroxine liberation and peptide hormone regulation. Elevated activity of cathepsin K has been associated with arthritis, atherosclerosis, obesity, schizophrenia, and tumor metastasis. Accordingly, its activity is tightly regulated via multiple mechanisms, including competitive inhibition by endogenous macromolecular inhibitors and allosteric regulation by glycosaminoglycans. This review provides a state-of-the-art description of the activity of cathepsin K at the molecular level, its biological functions and the mechanisms involved in its regulation.

Collagen Type I as a Ligand for Receptor-Mediated Signaling

“…Generally, a hydrophobic side chain such as valine, leucine, or proline is found in the second residue before the cleavage site, whereas the amino acid directly before the cleavage site is usually glutamic acid, alanine, or glycine. Finally, in the position after the cleavage site, the most common amino acids are glycine, glutamic acid, and/or isoleucine [87,89]. Overall, it has been found that cathepsin K performs a cleavage after helical cross-linking residues, which in collagen type I is most likely to occur after glycine due to high prevalence of GXY repeats [90].…”

“…Cathepsins that do not exhibit collagenase activity, such as cathepsins L, V, S, and B have only a limited effect on the fibril structures [96]. In addition to bone, cathepsin K is also expressed in hematopoietic, epithelial, and fibroblast cells, and was shown to play a role in arthritis, obesity, schizophrenia, bone metastases, and various other pathological conditions [89].…”

Regulation of TGF-β1-driven Differentiation of Human Lung Fibroblasts

“…Among various classes of proteases, there is now a growing body of evidence that cysteine cathepsins (Cats) participate in pulmonary homeostasis (8). Although their exact functions remain to be clarified, Cats are potent ECM-degrading enzymes (9,10). They belong to the family C1 (11 cysteine cathepsins for the human genome: cathepsins B, H, L, S, C, K, O, F, V, X, and W; see MEROPS: the peptidase database: (11)) and have long been thought to be primarily involved in lysosomal end stage degradation of endocytosed proteins (12).…”

Relevance of osteoclast-specific enzyme activities in cell-based in vitro resorption assays

“…Beside TRAP, which is proposed to finalise the degradation of organic bone matrix by reactive oxygen species and which is secreted together with the degradation products (Halleen et al, 1999), further osteoclast-specific enzymes are involved in osteoclastic resorption. CAII is responsible for the generation of protons in mature osteoclasts and cathepsin K (CTSK) is a very selective protease capable of cleaving collagen at several sites within the triple helix (Novinec and Lenarčič, 2013) and, therefore, a key player in osteoclastic matrix resorption. While TRAP activity has been quantified in numerous in vitro studies on osteoclast formation and differentiation, there are only few reports on the quantification of CAII activity for the evaluation of osteoclast function (Bernhardt et al, 2015;Detsch et al, 2010;Detsch et al, 2011) and CTSK activity has not yet been quantified to study osteoclastic resorption of biomaterials.…”