Further Insight into Mechanism of Action of Clodronate: Inhibition of Mitochondrial ADP/ATP Translocase by a Nonhydrolyzable, Adenine-Containing Metabolite
Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess bone resorption. Recent studies have shown that bisphosphonates can be divided into two groups with distinct molecular mechanisms of action depending on the nature of the R 2...
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Published in | Molecular pharmacology Vol. 61; no. 5; pp. 1255 - 1262 |
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Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.05.2002
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Subjects | |
Online Access | Get full text |
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Summary: | Bisphosphonates are currently the most important class of antiresorptive drugs used for the treatment of diseases with excess
bone resorption. Recent studies have shown that bisphosphonates can be divided into two groups with distinct molecular mechanisms
of action depending on the nature of the R 2 side chain. Alendronate, like other nitrogen-containing bisphosphonates, inhibits bone resorption and causes apoptosis of
osteoclasts and other cells in vitro by preventing post-translational modification of GTP-binding proteins with isoprenoid
lipids. Clodronate, a bisphosphonate that lacks a nitrogen, does not inhibit protein isoprenylation but can be metabolized
intracellularly to a β-γ-methylene (AppCp-type) analog of ATP, which is cytotoxic to macrophages in vitro. The detailed molecular
basis for the cytotoxic effects of adenosine-5â²-[β,γ-dichloromethylene]triphosphate (AppCCl 2 p) has not been determined yet. We addressed this question by studying the effects of alendronate, clodronate, and the clodronate
metabolite AppCCl 2 p on isolated mitochondria, mitochondrial fractions, and mitochondrial membrane potential in isolated human osteoclasts. We
found that AppCCl 2 p inhibits mitochondrial oxygen consumption by a mechanism that involves competitive inhibition of the ADP/ATP translocase.
Alendronate or the native form of clodronate did not have any immediate effect on mitochondria. However, longer treatment
with liposome-encapsulated clodronate caused collapse of the mitochondrial membrane potential, although prominent apoptosis
was a late event. Hence, inhibition of the ADP/ATP translocase by the metabolite AppCCl 2 p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption. |
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ISSN: | 0026-895X 1521-0111 |
DOI: | 10.1124/mol.61.5.1255 |