A novel approach to inhibit bone resorption: exosite inhibitors against cathepsin K.

Abstract

BACKGROUND AND PURPOSE:

Cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Potent active site-directed inhibitors have been developed and showed variable success in clinical trials. These inhibitors block the entire activity of CatK and thus may interfere with other pathways. The present study investigates the antiresorptive effect of an exosite inhibitor that selectively inhibits only the therapeutically relevant collagenase activity of CatK.

EXPERIMENTAL APPROACH:

Human osteoclasts and fibroblasts were used to analyse the effect of the exosite inhibitor, ortho-dihydrotanshinone (DHT1), and the active site inhibitor, odanacatib (ODN), on bone resorption and TGF-ß1 degradation. Cell cultures, Western blot, light and scanning electron microscopy as well as energy dispersive X-ray spectroscopy, molecular modelling and enzymatic assays were used to evaluate the inhibitors.

KEY RESULTS:

DHT1 selectively inhibited the collagenase activity of CatK, without affecting the viability of osteoclasts. Both inhibitors abolished the formation of resorption trenches, with DHT1 having a slightly higher IC50 value than ODN. Maximal reductions of other resorption parameters by DHT1 and ODN were comparable, respectively 41% and 33% for total resorption surface, 46% and 48% for resorption depths, and 83% and 61% for C-terminal telopetide fragment (CTX) release. DHT1 did not affect the turnover of fibrosis-associated TGF-ß1 in fibroblasts, whereas 500 nM ODN was inhibitory.

CONCLUSIONS AND IMPLICATIONS:

Our study shows that an exosite inhibitor of CatK can specifically block bone resorption without interfering with other pathways.

• Authors: Preety Panwar, Kent Søe, Rafael Vc Guido, Renata V C Bueno, Jean-Marie Delaisse, Dieter Brömme
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 173 Issue 2 Pg. 396-410 (Jan 2016) ISSN: 1476-5381 [Electronic] England
• PMID: 26562357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The British Pharmacological Society.

Chemical References

• Abietanes
• Biphenyl Compounds
• tanshinone
• Cathepsin K
• odanacatib

Topics

• Abietanes (metabolism, pharmacology, therapeutic use)
• Animals
• Biphenyl Compounds (metabolism, pharmacology, therapeutic use)
• Bone Resorption (drug therapy, metabolism)
• Cathepsin K (antagonists & inhibitors, chemistry, metabolism)
• Cattle
• Dose-Response Relationship, Drug
• Fibroblasts (drug effects, metabolism)
• Humans
• Osteoclasts (drug effects, metabolism)
• Protein Structure, Tertiary