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Tetracyclines induce apoptosis in osteoclasts
J T Bettany1, N M Peet, R G Wolowacz
1Smith & Nephew Group Research Centre, York Science Park, Heslington, UK.
Abstract:
Chemically modified tetracyclines (CMTs) are thought to inhibit bone resorption through inhibition of matrix metalloproteinases. Here we report that some tetracyclines also induce apoptosis in rabbit osteoclasts and inhibit differentiation and activity of osteoclasts in murine osteoblast/marrow cocultures. Apoptosis of mature rabbit osteoclasts increased from 5.5 +/- 1.4% (mean +/- SD) in control cultures to 44.9 +/- 6.3% (p < 0.001) and 18.9 +/- 4.0% (p < 0.005) with CMT-3 and doxycycline (10 microg/mL), respectively. CMT-2 or CMT-5 did not alter osteoclast viability even at 25 microg/mL. In murine osteoblast/marrow cocultures over 11 days, CMT-3 and doxycycline (5 microg/mL) reduced the formation of mature osteoclasts and inhibited resorption to 21 +/- 9% (p < 0.01) and 49 +/- 4% (p < 0.01) of untreated cultures. Induction of osteoclast apoptosis is an additional property of tetracyclines that may contribute to their ability to inhibit bone resorption.
Insights
Chemically modified tetracyclines (CMTs) induce osteoclast apoptosis and inhibit bone resorption. This apoptosis mechanism, demonstrated by CMT-3 and doxycycline, offers new insights into tetracycline
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Chemically modified tetracyclines (CMTs) are recognized for inhibiting bone resorption.
- Their mechanism is primarily attributed to the inhibition of matrix metalloproteinases.
Purpose of the Study:
- To investigate the potential of tetracyclines to induce apoptosis in osteoclasts.
- To evaluate the effect of specific CMTs and doxycycline on osteoclast differentiation and activity.
Main Methods:
- Treatment of mature rabbit osteoclasts with CMT-3 and doxycycline to assess apoptosis.
- Murine osteoblast/marrow cocultures were used to evaluate the impact of CMT-3 and doxycycline on osteoclast formation and resorption over 11 days.
Main Results:
- CMT-3 and doxycycline significantly increased osteoclast apoptosis in rabbit osteoclast cultures.
- CMT-3 and doxycycline reduced mature osteoclast formation and inhibited bone resorption in murine cocultures.
- CMT-2 and CMT-5 did not demonstrate significant effects on osteoclast viability.
Conclusions:
- Tetracyclines, including specific CMTs and doxycycline, possess the ability to induce osteoclast apoptosis.
- Osteoclast apoptosis is an additional mechanism contributing to the bone resorption inhibitory effects of tetracyclines.