RT Journal Article
SR Electronic
T1 Further Insight into Mechanism of Action of Clodronate: Inhibition of Mitochondrial ADP/ATP Translocase by a Nonhydrolyzable, Adenine-Containing Metabolite
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1255
OP 1262
DO 10.1124/mol.61.5.1255
VO 61
IS 5
A1 Petri P. Lehenkari
A1 Maarit Kellinsalmi
A1 Juha P. Näpänkangas
A1 Kari V. Ylitalo
A1 Jukka Mönkkönen
A1 Michael J. Rogers
A1 Alex Azhayev
A1 H. Kalervo Väänänen
A1 Ilmo E. Hassinen
YR 2002
UL http://molpharm.aspetjournals.org/content/61/5/1255.abstract
AB 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 R2 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-5′-[β,γ-dichloromethylene]triphosphate (AppCCl2p) has not been determined yet. We addressed this question by studying the effects of alendronate, clodronate, and the clodronate metabolite AppCCl2p on isolated mitochondria, mitochondrial fractions, and mitochondrial membrane potential in isolated human osteoclasts. We found that AppCCl2p 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 AppCCl2p is a likely route by which clodronate causes osteoclast apoptosis and inhibits bone resorption.