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Titolo:
Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro
Autore:
Benford, HL; McGowan, NWA; Helfrich, MH; Nuttall, ME; Rogers, MJ;
Indirizzi:
Univ Aberdeen, Sch Med, Dept Med & Therapeut, Aberdeen AB25 2ZD, Scotland Univ Aberdeen Aberdeen Scotland AB25 2ZD ut, Aberdeen AB25 2ZD, Scotland SmithKline Beecham Pharmaceut, King Of Prussia, PA 19406 USA SmithKline Beecham Pharmaceut King Of Prussia PA USA 19406 , PA 19406 USA
Titolo Testata:
BONE
fascicolo: 5, volume: 28, anno: 2001,
pagine: 465 - 473
SICI:
8756-3282(200105)28:5<465:VOBCAI>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
NITROGEN-CONTAINING BISPHOSPHONATES; INHIBIT BONE-RESORPTION; MOLD DICTYOSTELIUM-DISCOIDEUM; CELLS IN-VITRO; MEVALONATE PATHWAY; PROTEIN GERANYLGERANYLATION; ADENINE-NUCLEOTIDES; BINDING PROTEINS; FACTOR RECEPTOR; ACTIVATION;
Keywords:
bisphosphonate; osteoclast; caspase; apoptosis; prenylation; GGTI-298;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
54
Recensione:
Indirizzi per estratti:
Indirizzo: Rogers, MJ Univ Aberdeen, Sch Med, Dept Med & Therapeut, Polwarth Bldg, Aberdeen AB252ZD, Scotland Univ Aberdeen Polwarth Bldg Aberdeen Scotland AB25 2ZD cotland
Citazione:
H.L. Benford et al., "Visualization of bisphosphonate-induced caspase-3 activity in apoptotic osteoclasts in vitro", BONE, 28(5), 2001, pp. 465-473

Abstract

Bisphosphonates inhibit osteoclast-mediated bone resorption by mechanisms that have only recently become clear. Whereas nitrogen-containing bisphosphonates affect osteoclast function by preventing protein prenylation (especially geranylgeranylation), non-nitrogen-containing bisphosphonates have a different molecular mechanism of action. In this study, we demonstrate that nitrogen-containing bisphosphonates (risedronate, alendronate, pamidronate,and zoledronic acid) and non-nitrogen-containing bisphosphonates (clodronate and etidronate) cause apoptosis of rabbit osteoclasts, human osteoclastoma-derived osteoclasts, and human osteoclast-like cells generated in cultures of bone marrow in vitro. Osteoclast apoptosis was shown to involve characteristic morphological changes, loss of mitochondrial membrane potential, and the activation of caspase-3-like proteases capable of cleaving peptide substrates with the sequence DEVD, Caspase-3-like activity could be visualized in unfixed, dying osteoclasts and osteoclast-like cells using a cell-permeable, fluorogenic substrate, Bisphosphonate-induced osteoclast apoptosiswas dependent on caspase activation, because apoptosis resulting from alendronate, clodronate, or zoledronic acid treatment was suppressed by zVAD-fmk, a broad-range caspase inhibitor, or by SB-281277, a specific isatin sulfonamide inhibitor of caspase-3/-7, Furthermore, caspase-3 (but not caspase-6 or caspase-7) activity could be detected and quantitated in lysates from purified rabbit osteoclasts, whereas the p17 fragment of active caspase-3 could be detected in human osteoclast-like cells by immunofluorescence staining, Caspase-3, therefore, appears to be the major effector caspase activated in osteoclasts by bisphosphonate treatment, Caspase activation and apoptosis induced by nitrogen-containing bisphosphonates are likely to be the consequence of the loss of geranylgeranylated rather than farnesylated proteins, because the ability to cause apoptosis and caspase activation was mimicked by GGTI-298, a specific inhibitor of protein geranylgeranylation, whereas FTI-277, a specific inhibitor of protein farnesylation, had no effect onapoptosis or caspase activity. (C) 2001 by Elsevier Science Inc. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 18:20:36