title: The effects of the cathepsin K inhibitor odanacatib on osteoclastic bone resorption and vesicular trafficking.
abstract: Odanacatib (ODN) is a selective, potent and reversible inhibitor of cathepsin K (CatK) that inhibits bone loss in postmenopausal osteoporosis. Evidence from osteoclast (OC) formation from bone marrow of CatK(-/-) mice or human OC progenitors treated with ODN, demonstrated that CatK inhibition has no effect on osteoclastogenesis or survival of OCs. Although having no impact on OC activation, ODN reduces resorption activity as measured by CTx release (IC(50)=9.4 nM) or resorption area (IC(50)=6.5 nM). While untreated cells generate deep trail-like resorption lacunae, treated OCs form small discrete shallow pits. ODN leads to significant accumulation of intracellular vesicles intensely stained for CatK and TRAP. CatK (+) vesicles localize toward the basolateral and functional secretory membranes of the polarized OC and TRAP(+) vesicles evenly distribute in the cytoplasm, suggesting that ODN disrupts multiple vesicular trafficking pathways. Intracellular levels of both precursor and mature TRAP were increased by 2-fold and the pre-pro and mature CatK by 6- and 2-fold in ODN-treated OCs compared to untreated controls. ODN treated OC accumulates labeled degraded bone matrix proteins in CatK containing vesicles. In summary, ODN treatment inhibits bone resorption by blocking degradation of demineralized collagen in the resorption lacunae, and retarding transcytosis for further processing of degraded proteins.
authors: Merck Sharp, & Dohme Corp., P.O. Box 100, Whitehouse Station, NJ 08889, USA.
authors: P
authors: P
authors: Leung
authors: M
authors: M
authors: Pickarski
authors: Y
authors: Y
authors: Zhuo
authors: P J
authors: PJ
authors: Masarachia
authors: L T
authors: LT
authors: Duong
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001857:Bone Matrix / Q000187:drug effects / Q000378:metabolism; D001862:Bone Resorption / Q000201:enzymology / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D016764:Cell Polarity / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D010012:Osteogenesis / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase; D022161:Transport Vesicles / Q000187:drug effects* / Q000201:enzymology
chemical_list: D001713:Biphenyl Compounds; D007527:Isoenzymes; D011480:Protease Inhibitors; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; C527128:odanacatib