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.