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 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 (2-3h), whereas alendronate-induced apoptosis was delayed (>12h). 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.
Holmes
Simon
S
Section of Musculoskeletal Science, School of Medicine, University of Sheffield, UK.
Smith
Susan
S
Borthwick
Lee
L
Dunford
James
J
Rogers
Mike
M
Bishop
Nick
N
Grabowski
Peter S
PS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure*; D013754:Tetracyclines / Q000008:administration & dosage*
D013754:Tetracyclines