CMT3 alters mitochondrial function in murine osteoclast lineage cells

Simon Holmes, Susan Smith, Lee Borthwick, James Edward Dunford, Mike Rogers, Nick Bishop, Peter S. Grabowski

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    8 Citations (Scopus)


    Chemically modified tetracyclines (CMTs 1-10) were developed as non-antibiotic inhibitors of matrix metalloproteinases (MMPs). We previously demonstrated that MMP inhibition alone is insufficient to explain the pro-apoptotic action of CMTs in osteoclast lineage cells and we have explored additional mechanisms of action. We compared the characteristics of apoptosis in RAW264.7 murine monocyte and osteoclast cultures treated with pharmacologically relevant concentrations of CMT3 or the bisphosphonate alendronate, which induces osteoclast apoptosis through inhibition of farnesyl diphosphate synthase. CMT3 induced apoptosis rapidly (2-3 h), whereas alendronate-induced apoptosis was delayed (>12 h). CMT3-treated cells did not accumulate unprenylated Rap1A in contrast to cells treated with alendronate. Importantly, CMT3 induced a rapid loss of mitochondrial stability in RAW264.7 cells measured by loss of Mitotracker(R) Red fluorescence, while bongkrekic acid protected polykaryons from CMT3-induced apoptosis. Modulation of mitochondrial function is therefore a significant early action of CMT3 that promotes apoptosis in osteoclast lineage cells. (C) 2007 Elsevier Inc. All rights reserved.

    Original languageEnglish
    Pages (from-to)840-845
    Number of pages6
    JournalBiochemical and Biophysical Research Communications
    Issue number4
    Early online date26 Nov 2007
    Publication statusPublished - 25 Jan 2008


    • chemically modified tetracyclines
    • CMT3
    • COL3
    • apoptosis
    • RAW264.7
    • osteoclast
    • mitochondrial transition pore
    • bisphosphonates
    • prenylation
    • bongkrekic acid
    • nitrogen-containing bisphosphonates
    • matrix-metalloproteinase inhibitor
    • in-vitro
    • molecular-mechanism
    • induce apoptosis
    • bone-resorption
    • activation
    • COL-3
    • tetracyclines
    • cancer


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