CMT3 alters mitochondrial function in murine osteoclast lineage cells

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...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2008-01, Vol.365 (4), p.840-845
Main Authors: Holmes, Simon, Smith, Susan, Borthwick, Lee, Dunford, James, Rogers, Mike, Bishop, Nick, Grabowski, Peter S.
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Bisphosphonates
Bongkrekic acid
Cell Line
Cell Proliferation - drug effects
Cell Survival - drug effects
Chemically modified tetracyclines
CMT3
COL3
Dose-Response Relationship, Drug
Mice
Mitochondria - drug effects
Mitochondria - physiology
Mitochondrial transition pore
Osteoclast
Osteoclasts - drug effects
Osteoclasts - physiology
Osteoclasts - ultrastructure
Prenylation
RAW264.7
Tetracyclines - administration & dosage
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Summary: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 ® 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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2007.11.054