Linked Life Data

20097319

Source:http://linkedlifedata.com/resource/pubmed/id/20097319

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2010-4-12
pubmed:abstractText
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 inhibitors of catK to suppress bone resorption by human osteoclasts. We found that basic compounds were considerably more potent than non-basic compounds at suppression of osteoclastic resorption than would be anticipated from their potency as enzyme inhibitors. Also consistent with osteoclastic lysosomotropism, basic inhibitors suppressed resorption for substantially longer than a non-basic inhibitor after washout from cell cultures. Furthermore, selectivity of basic inhibitors for inhibition of catK versus other cathepsins persisted: concentrations that inhibited catK in osteoclasts had no detectable effect on cathepsin S (catS) in a cell-based assay. This data is consistent with accumulation and enrichment of such basic inhibitors in the resorptive apparatus of the osteoclast, allowing for prolonged efficacy at the intended site of action. Our results suggest a major advantage for lysosomotropic compounds as inhibitors of bone resorption by osteoclasts in osteoporosis and other diseases caused by excessive osteoclastic activity.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
1873-2763
pubmed:author
pubmed:copyrightInfo
Copyright (c) 2010 Elsevier Inc. All rights reserved.
pubmed:issnType
Electronic
pubmed:volume
46
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1400-7
pubmed:meshHeading
pubmed:year
2010
pubmed:articleTitle
The resorptive apparatus of osteoclasts supports lysosomotropism and increases potency of basic versus non-basic inhibitors of cathepsin K.
pubmed:affiliation
Department of Cellular Pathology, St George's, University of London, Cranmer Terrace, Tooting, London, UK.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't