title: BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-kappaB activation.
abstract: The signal transduction pathway by which bone morphogenetic protein-2 (BMP-2) regulates apoptosis in chondrocytes remains largely unknown. We investigated the involvement of phosphatidylinositol 3-kinase (PI3K)/Akt-mediated NF-kappaB activation by BMP-2 stimulation in the modulation of this antiapoptotic process in a chondrocytic cell line, N1511. BMP-2 prevented apoptosis through the inhibition of caspase-3 and -9 and an increase in Bcl-xL expression, and this antiapoptotic effect was inhibited by Noggin. Not only was NF-kappaB p65 activated transiently in the early phase (5-15 min) after treatment with BMP-2 but p65 at serine 536 was phosphorylated from 5 min as well. Akt was rapidly phosphorylated in response to BMP-2 treatment; however, the inhibition of PI3K by Wortmannin markedly reduced the phosphorylation of Akt by BMP-2. Wortmannin also decreased the NF-kappaB transcriptional activity that was up-regulated by BMP-2. Thus, BMP-2-induced NF-kappaB activation is mediated by PI3K/Akt signaling. Wortmannin treatment inhibited the antiapoptotic effect of BMP-2. These data indicate that BMP-2 can utilize a new signal transduction pathway in the NF-kappaB activation system, which plays a crucial role in the survival of the N1511 chondrocytic cell line.
authors.affiliation: Department of Orthopaedic Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Sugimori
authors.forename: Koshi
authors.initials: K
authors.lastname: Matsui
authors.forename: Hiraku
authors.initials: H
authors.lastname: Motomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokoro
authors.forename: Juyong
authors.initials: J
authors.lastname: Wang
authors.forename: Susumu
authors.initials: S
authors.lastname: Higa
authors.forename: Tomoatsu
authors.initials: T
authors.lastname: Kimura
authors.forename: Isao
authors.initials: I
authors.lastname: Kitajima
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology / Q000502:physiology*; D002352:Carrier Proteins / Q000494:pharmacology; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects / Q000502:physiology; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*; D000077191:Wortmannin; D051020:bcl-X Protein / Q000096:biosynthesis; D000099176:Noggin Protein
chemical_list: D000730:Androstadienes; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; D016212:Transforming Growth Factor beta; D000077191:Wortmannin; D051020:bcl-X Protein; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C498144:Rela protein, mouse; C505407:CASP3 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C506434:Casp9 protein, mouse