Skip to main content
SpringerLink
Log in

BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-κB activation

  • ORIGINAL ARTICLE
  • Published:
Journal of Bone and Mineral Metabolism Aims and scope Submit manuscript

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-κB 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-κB 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-κB transcriptional activity that was up-regulated by BMP-2. Thus, BMP-2-induced NF-κB 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-κB activation system, which plays a crucial role in the survival of the N1511 chondrocytic cell line.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. WA Horton (2003) ArticleTitleThe biology of bone growth Lancet 362 560–569 Occurrence Handle10.1016/S0140-6736(03)14119-0 Occurrence Handle12932391

    Article  PubMed  Google Scholar 

  2. M Izumi Y Fujio K Kunisada S Negoro E Tone M Funamoto T Osugi Y Oshima Y Nakaoka T Kishimoto K Yamauchi-Takihara H Hirota (2001) ArticleTitleBone morphogenetic protein-2 inhibits serum deprivation-induced apoptosis of neonatal cardiac myocytes through activation of the Smad1 pathway J Biol Chem 276 31133–31141 Occurrence Handle10.1074/jbc.M101463200 Occurrence Handle11408477

    Article  PubMed  Google Scholar 

  3. S Chen DC Guttridge E Tang S Shi K Guan CY Wang (2001) ArticleTitleSuppression of tumor necrosis factor-mediated apoptosis by nuclear factor kappa B-independent bone morphogenetic protein/Smad signaling J Biol Chem 276 39259–39263 Occurrence Handle10.1074/jbc.M105335200 Occurrence Handle11500509

    Article  PubMed  Google Scholar 

  4. E Hay J Lemonnier O Fromigue PJ Marie (2001) ArticleTitleBone morphogenetic protein-2 promotes osteoblast apoptosis through a Smad-independent, protein kinase C-dependent signaling pathway J Biol Chem 276 29028–29036 Occurrence Handle10.1074/jbc.M011265200 Occurrence Handle11395480

    Article  PubMed  Google Scholar 

  5. E Kolettas HI Muir JC Barrett TE Hardingham (2001) ArticleTitleChondrocyte phenotype and cell survival are regulated by culture conditions and by specific cytokines through the expression of Sox-9 transcription factor Rheumatology (Oxford) 40 1146–1156 Occurrence Handle10.1093/rheumatology/40.10.1146

    Article  Google Scholar 

  6. R Venezian BJ Shenker S Datar PS Leboy (1998) ArticleTitleModulation of chondrocyte proliferation by ascorbic acid and BMP-2 J Cell Physiol 174 331–341 Occurrence Handle10.1002/(SICI)1097-4652(199803)174:3<331::AID-JCP7>3.0.CO;2-P Occurrence Handle9462695

    Article  PubMed  Google Scholar 

  7. N Ghosh-Choudhury SL Abboud R Nishimura A Celeste L Mahimainathan GG Choudhury (2002) ArticleTitleRequirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription J Biol Chem 277 33361–33368 Occurrence Handle10.1074/jbc.M205053200 Occurrence Handle12084724

    Article  PubMed  Google Scholar 

  8. TF Franke LC Cantley (1997) ArticleTitleA Bad kinase makes good Nature 390 116–117 Occurrence Handle10.1038/36442 Occurrence Handle9367147

    Article  PubMed  Google Scholar 

  9. A Toker LC Cantley (1997) ArticleTitleSignalling through the lipid products of phosphoinositide-3-OH kinase Nature 387 673–676 Occurrence Handle10.1038/42648 Occurrence Handle9192891

    Article  PubMed  Google Scholar 

  10. SR Datta A Brunnet ME Greenberg (1999) ArticleTitleCellular survival: a play in three Akts Genes Dev 13 2905–2927 Occurrence Handle10.1101/gad.13.22.2905 Occurrence Handle10579998

    Article  PubMed  Google Scholar 

  11. MH Cardone N Roy HR Stennicke GS Salvesen TF Franke E Stanbridge S Frisch JC Reed (1998) ArticleTitleRegulation of cell death protease caspase-9 by phosphorylation Science 282 1318–1321 Occurrence Handle10.1126/science.282.5392.1318 Occurrence Handle9812896

    Article  PubMed  Google Scholar 

  12. LV Madrid CY Wang DC Guttridge AJ Schottelius AS Baldwin SuffixJr MW Mayo (2000) ArticleTitleAkt suppresses apoptosis by stimulating the transactivation potential of the RelA/p65 subunit of NF-kappa B Mol Cell Biol 20 1626–1638 Occurrence Handle10.1128/MCB.20.5.1626-1638.2000 Occurrence Handle10669740

    Article  PubMed  Google Scholar 

  13. LV Madrid MW Mayo JY Reuther AS Baldwin SuffixJr (2001) ArticleTitleAkt stimulates the transactivation potential of the RelA/p65 subunit of NF-kappa B through utilization of the I kappa B kinase and activation of the mitogen-activated protein kinase p38 J Biol Chem 276 18934–18940 Occurrence Handle10.1074/jbc.M101103200 Occurrence Handle11259436

    Article  PubMed  Google Scholar 

  14. N Kamiya A Jikko K Kimata C Damsky K Shimizu H Watanabe (2002) ArticleTitleEstablishment of a novel chondrocytic cell line N1511 derived from p53-null mice J Bone Miner Res 17 1832–1842 Occurrence Handle12369787

    PubMed  Google Scholar 

  15. TT Huang N Kudo M Yoshida S Miyamoto (2000) ArticleTitleA nuclear export signal in the N-terminal regulatory domain of I kappaBalpha controls cytoplasmic localization of inactive NF-kappa B/IkappaBalpha complexes Proc Natl Acad Sci USA 97 1014–1019 Occurrence Handle10.1073/pnas.97.3.1014 Occurrence Handle10655476

    Article  PubMed  Google Scholar 

  16. I Kitajima T Shinohara J Bilakovics DA Brown X Xu M Nerenberg (1992) ArticleTitleAblation of transplanted HTLV-I Tax-transformed tumors in mice by antisense inhibition of NF-kappa B Science 258 1792–1795 Occurrence Handle1299224

    PubMed  Google Scholar 

  17. RH Arch RW Gedrich CB Thompson (1998) ArticleTitleTumor necrosis factor receptor-associated factors (TRAFs) – a family of adapter proteins that regulates life and death Genes Dev 12 2821–2830 Occurrence Handle9744859

    PubMed  Google Scholar 

  18. O Micheau S Lens O Gaide K Alevizopoulos J Tschopp (2001) ArticleTitleNF-kappa B signals induce the expression of c-FLIP Mol Cell Biol 21 5299–5305 Occurrence Handle10.1128/MCB.21.16.5299-5305.2001 Occurrence Handle11463813

    Article  PubMed  Google Scholar 

  19. E Hatano DA Brenner (2002) ArticleTitleAkt protects mouse hepatocytes from TNF-alpha- and Fas-mediated apoptosis through NF-kappa B activation Am J Physiol Gastrointest Liver Physiol 282 G1357–G1368

    Google Scholar 

  20. YI Lee S Kang-Park SI Do YI Lee (2001) ArticleTitleThe hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade J Biol Chem 276 16969–16977 Occurrence Handle10.1074/jbc.M011263200 Occurrence Handle11278872

    Article  PubMed  Google Scholar 

  21. CH Heldin K Miyazono P ten Dijke (1997) ArticleTitleTGF-beta signalling from cell membrane to nucleus through SMAD proteins Nature 390 465–471 Occurrence Handle10.1038/37284 Occurrence Handle9393997

    Article  PubMed  Google Scholar 

  22. M Fujii K Takeda T Imamura H Aoki TK Sampath S Enomoto M Kawabata M Kato H Ichijo K Miyazono (1999) ArticleTitleRoles of bone morphogenetic protein type I receptors and Smad proteins in osteoblast and chondroblast differentiation Mol Biol Cell 10 3801–3813 Occurrence Handle10564272

    PubMed  Google Scholar 

  23. MT Hartsough KM Mulder (1995) ArticleTitleTransforming growth factor beta activation of p44mapk in proliferating cultures of epithelial cells J Biol Chem 270 7117–7124 Occurrence Handle10.1074/jbc.270.13.7117 Occurrence Handle7706248

    Article  PubMed  Google Scholar 

  24. A Atfi S Djelloul E Chastre R Davis C Gespach (1997) ArticleTitleEvidence for a role of Rho-like GTPases and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in transforming growth factor beta-mediated signaling J Biol Chem 272 1429–1432 Occurrence Handle10.1074/jbc.272.40.24731 Occurrence Handle8999807

    Article  PubMed  Google Scholar 

  25. M Hannigan L Zhan Y Ai CK Huang (1998) ArticleTitleThe role of p38 MAP kinase in TGF-beta1-induced signal transduction in human neutrophils Biochem Biophys Res Commun 246 55–58 Occurrence Handle10.1006/bbrc.1998.8570 Occurrence Handle9600067

    Article  PubMed  Google Scholar 

  26. E Ainbinder M Revach O Wolstein S Moshonov N Diamant R Dikstein (2002) ArticleTitleMechanism of rapid transcriptional induction of tumor necrosis factor alpha-responsive genes by NF-kappa B Mol Cell Biol 22 6354–6362 Occurrence Handle10.1128/MCB.22.18.6354-6362.2002 Occurrence Handle12192035

    Article  PubMed  Google Scholar 

  27. DJ Van Antwerp SJ Martin T Kafri DR Green IM Verma (1996) ArticleTitleSuppression of TNF-alpha-induced apoptosis by NF-kappa B Science 274 787–789 Occurrence Handle10.1126/science.274.5288.787 Occurrence Handle8864120

    Article  PubMed  Google Scholar 

  28. H Sakurai H Chiba H Miyoshi T Sugita W Toriumi (1999) ArticleTitleI kappa B kinases phosphorylate NF-kappa B p65 subunit on serine 536 in the transactivation domain J Biol Chem 274 30353–30356 Occurrence Handle10.1074/jbc.274.43.30353 Occurrence Handle10521409

    Article  PubMed  Google Scholar 

  29. AA Beg WC Sha RT Bronson S Ghosh D Baltimore (1995) ArticleTitleEmbryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B Nature 376 167–170 Occurrence Handle10.1038/376167a0 Occurrence Handle7603567

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Orthopaedic Surgery, Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan

    Kazuhito Sugimori, Hiraku Motomura & Tomoatsu Kimura

  2. Department of Laboratory Medicine, Faculty of Medicine, 21st Century COE Program, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama, 930-0194, Japan

    Kazuhito Sugimori, Koshi Matsui, Hiraku Motomura, Takashi Tokoro, Juyong Wang, Susumu Higa & Isao Kitajima

Authors
  1. Kazuhito Sugimori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Koshi Matsui
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiraku Motomura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takashi Tokoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Juyong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susumu Higa
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoatsu Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Isao Kitajima
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Isao Kitajima.

About this article

Cite this article

Sugimori, K., Matsui, K., Motomura, H. et al. BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-κB activation. J Bone Miner Metab 23, 411–419 (2005). https://doi.org/10.1007/s00774-005-0622-7

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00774-005-0622-7

Key words

Search

Navigation