The resorptive apparatus of osteoclasts supports lysosomotropism and increases potency of basic versus non-basic inhibitors of cathepsin K

Bone
K FullerTimothy J Chambers

Abstract

In mice and humans, the effect of genetic deficiency of cathepsin K (catK) is impaired bone resorption, or osteopetrosis. Inhibition of catK is therefore a promising strategy for the treatment of osteoporosis. The enzyme acts in an acid environment. This provides a further potential opportunity: if the inhibitor is basic it is more likely to accumulate in membrane-bound acidic compartments (lysosomotropism), so minimizing off-target effects. However, the resorptive hemivacuole is not membrane-bound, and so might not retain lysosomotropic compounds. We therefore elected to determine whether the osteoclastic resorptive apparatus supports such accumulation. First, we attempted to compare the persistence of a lysosomotropic dye in the hemivacuole versus intracellular vesicles. To our surprise the dye could not be detected in the ruffled border region by confocal microscopy. We found that this could be explained by the tight packing of the folds of the ruffled border, and their close apposition to the bone surface. We also found that the dye persisted similarly in resorbing osteoclasts and macrophages, consistent with the notion that resorbing osteoclasts support lysosomotropism. Next, we compared the ability of basic and non-basic ...Continue Reading

References

Jul 15, 1991·Biochemical and Biophysical Research Communications·C J van Noorden, V Everts
Nov 1, 1988·Biopharmaceutics & Drug Disposition·A C MacIntyre, D J Cutler
Apr 1, 1988·Experimental Cell Research·I A SilverD J Etherington
Mar 1, 1988·Journal of Pharmaceutical Sciences·A C MacIntyre, D J Cutler
Sep 15, 1974·Biochemical Pharmacology·C de DuveF Van Hoof
Mar 1, 1984·Journal of Cell Science·T J ChambersN A Athanasou
Apr 1, 1997·Journal of Anatomy·T AkisakaM Inoue
Nov 13, 1998·Proceedings of the National Academy of Sciences of the United States of America·P SaftigK von Figura
Sep 2, 1999·Human Molecular Genetics·F LaznerI Kola
Sep 24, 2002·Seminars in Cell & Developmental Biology·Gudrun Stenbeck
Oct 21, 2003·The Journal of Pharmacology and Experimental Therapeutics·Robin L ThurmondLars Karlsson
Dec 31, 2005·Endocrinology·Karen FullerTimothy J Chambers
Aug 22, 2006·Chembiochem : a European Journal of Chemical Biology·W Cameron Black, M David Percival
Nov 9, 2006·Journal of Translational Medicine·Barrie KirsteinKaren Fuller
Nov 23, 2006·Journal of Pharmaceutical Sciences·Allyn M Kaufmann, Jeffrey P Krise
Jan 24, 2007·Clinical Science·Karen FullerTimothy J Chambers

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Citations

Oct 26, 2013·Expert Opinion on Pharmacotherapy·Roland D Chapurlat
Jan 25, 2014·Expert Opinion on Pharmacotherapy·Roland D Chapurlat
Jun 2, 2015·Therapeutic Advances in Musculoskeletal Disease·Roland D Chapurlat
May 11, 2018·Journal of Translational Medicine·Erik LindströmUrszula Grabowska

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