title: Distinguishing the proapoptotic and antiresorptive functions of risedronate in murine osteoclasts: role of the Akt pathway and the ERK/Bim axis.
abstract: OBJECTIVE
  Nitrogen-containing bisphosphonates are one of the most successful therapeutics for osteoporosis. The aim of this study was to elucidate the functional mechanism of one of the typical nitrogen-containing bisphosphonates, risedronate.
  
  
  METHODS
  Osteoclasts generated from murine bone marrow macrophages were treated with risedronate in vitro, and its effects on apoptosis and bone-resorbing activity were examined. The mechanism of action of risedronate was examined by gene induction of constitutively active Akt-1 and constitutively active MEK-1, and by gene deletion of Bim. Bim(-/-)  mice, in which osteoclasts were resistant to apoptosis, were treated with risedronate and analyzed radiographically, biochemically, and histologically.
  
  
  RESULTS
  Risedronate induced osteoclast apoptosis through the mitochondria-dependent pathway with an increased expression of Bim, and the proapoptotic effect of risedronate was suppressed by Bim deletion and constitutively active MEK-1 introduction. In contrast, the risedronate-induced suppression of bone resorption was completely reversed by inducing constitutively active Akt-1, but not by Bim deletion or constitutively active MEK-1 introduction. These results suggested that apoptosis and bone-resorbing activity of osteoclasts were regulated through the ERK/Bim axis and the Akt pathway, respectively, both of which were suppressed by risedronate. Although osteoclast apoptosis in response to risedronate administration was suppressed in the Bim(-/-)  mice, risedronate treatment increased bone mineral density in Bim(-/-)  mice at a level equivalent to that in wild-type mice.
  
  
  CONCLUSIONS
  Our findings indicate that the antiresorptive effect of risedronate in vivo is mainly mediated by the suppression of the bone-resorbing activity of osteoclasts and not by the induction of osteoclast apoptosis.
authors: University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors: Takumi
authors: T
authors: Matsumoto
authors: Yuichi
authors: Y
authors: Nagase
authors: Mitsuyasu
authors: M
authors: Iwasawa
authors: Tetsuro
authors: T
authors: Yasui
authors: Hironari
authors: H
authors: Masuda
authors: Yuho
authors: Y
authors: Kadono
authors: Kozo
authors: K
authors: Nakamura
authors: Sakae
authors: S
authors: Tanaka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D015519:Bone Density / Q000187:drug effects / Q000502:physiology; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001862:Bone Resorption / Q000503:physiopathology*; D002478:Cells, Cultured; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D017353:Gene Deletion; D066298:In Vitro Techniques; D048369:MAP Kinase Kinase 1 / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D023421:Models, Animal; D010010:Osteoclasts / Q000187:drug effects* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D000068296:Risedronic Acid; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D050071:Bone Density Conservation Agents; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D000068296:Risedronic Acid; D012968:Etidronic Acid