Cathepsin K inhibitors for osteoporosis and potential off-target effects

Abstract

Cathepsin K is a highly potent collagenase and the predominant papain-like cysteine protease expressed in osteoclasts. Cathepsin K deficiencies in humans and mice have underlined the central role of this protease in bone resorption and, thus, have rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. In the past decade, a lot of efforts have been made in developing highly potent, selective and orally applicable cathepsin K inhibitors. Some of these inhibitors have passed preclinical studies and are presently in clinical trials at different stages of advancement. The development of the inhibitors and preliminary results of the clinical trials revealed problems and lessons concerning the in situ specificity of the compounds and their tissue targeting. In this review, we briefly summarize the history of cathepsin K research and discuss the current development of cathepsin K inhibitors as novel anti-resorptives for the treatment of osteoporosis. We also discuss potential off-target effects of cathepsin K inhibition and alternative applications of cathepsin K inhibitors in arthritis, atherosclerosis, blood pressure regulation, obesity and cancer.

Figure 1

A) Schematic representation of the degradation of triple helical collagens by cathepsin K (random cleavage sites) and matrix metallo proteinases (one cleavage site). B) Electron microscopy images (osmium staining) of human RA-synovial fibroblasts cultivated on bovine cartilage discs (original magnification ×10,000). The left panel shows the inhibition of fibrillar collagen degradation in a synovial fibroblast by the potent cathepsin K inhibitor LHVS (accumulation of undigested collagen fibrils in lysosomal/endosomal vesicles; see arrows). The right panel shows the lack of inhibition of collagen degradation in the presence of the potent cathepsins S, L and B but ineffective cathepsin K inhibitor, Mu-hPhe-Np-VSNp (no intracellular accumulation of striated collagen fibrils) [145,35].

Figure 2

Physiological and pathophysiological implications of cathepsin K (expressed or not) in mammals. Cancers or related diseases are in italic. Potential consequences of a treatment with a cathepsin K inhibitor are indicated (left panel: off-target; right panel: therapeutic target for osteoporosis and other diseases).

Figure 3

Drug development strategies for osteoporosis therapy: A) systemic interference (Hormone replacement therapy), B) osteoclast cell targeting (apoptosis of osteoclasts by bisphosphonates), C) single molecular function targeting (prevention of bone collagen matrix degradation by cathepsin K inhibition).