title: Bisphosphonates act directly on the osteoclast to induce caspase cleavage of mst1 kinase during apoptosis. A link between inhibition of the mevalonate pathway and regulation of an apoptosis-promoting kinase.
abstract: Bisphosphonates (BPs) include potent inhibitors of bone resorption used to treat osteoporosis and other bone diseases. BPs directly or indirectly induce apoptosis in osteoclasts, the bone resorbing cells, and this may play a role in inhibition of bone resorption. Little is known about downstream mediators of apoptosis in osteoclasts, which are difficult to culture. Using purified osteoclasts, we examined the effects of alendronate, risedronate, pamidronate, etidronate, and clodronate on apoptosis and signaling kinases. All BPs induce caspase-dependent formation of pyknotic nuclei and cleavage of Mammalian Sterile 20-like (Mst) kinase 1 to form the active 34-kDa species associated with apoptosis. Withdrawal of serum and of macrophage colony stimulating factor, necessary for survival of purified osteoclasts, or treatment with staurosporine also induce apoptosis and caspase cleavage of Mst1. Consistent with their inhibition of the mevalonate pathway, apoptosis and cleavage of Mst1 kinase induced by alendronate, risedronate, and lovastatin, but not clodronate, are blocked by geranylgeraniol, a precursor of geranylgeranyl diphosphate. Together these findings suggest that BPs act directly on the osteoclast to induce apoptosis and that caspase cleavage of Mst1 kinase is part of the apoptotic pathway. For alendronate and risedronate, these events seem to be downstream of inhibition of geranylgeranylation.
authors.affiliation: Department of Bone Biology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. Alfred_Reszka@merck.com
authors.forename: A A
authors.initials: AA
authors.lastname: Reszka
authors.forename: J M
authors.initials: JM
authors.lastname: Halasy-Nagy
authors.forename: P J
authors.initials: PJ
authors.lastname: Masarachia
authors.forename: G A
authors.initials: GA
authors.lastname: Rodan
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002121:Calcium Channel Blockers / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D004002:Clodronic Acid / Q000494:pharmacology; D004164:Diphosphonates / Q000378:metabolism*; D004224:Diterpenes / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D017368:Protein Prenylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000068296:Risedronic Acid; D015398:Signal Transduction / Q000187:drug effects; D019311:Staurosporine / Q000378:metabolism; D013997:Time Factors; D000099317:Hippo Kinases
chemical_list: D019386:Alendronate; D002121:Calcium Channel Blockers; D061945:Caspase Inhibitors; D020169:Caspases; D004002:Clodronic Acid; D004164:Diphosphonates; D004224:Diterpenes; D012968:Etidronic Acid; D020930:MAP Kinase Kinase Kinases; D016173:Macrophage Colony-Stimulating Factor; D008798:Mevalonic Acid; D017346:Protein Serine-Threonine Kinases; D000068296:Risedronic Acid; D019311:Staurosporine; C017338:geranylgeraniol; C490660:Stk4 protein, mouse; D000099317:Hippo Kinases; C490541:Map3k10 protein, mouse