Advertisement

Molecular and Cellular Biochemistry

, Volume 409, Issue 1–2, pp 51–58 | Cite as

Edaravone protects osteoblastic cells from dexamethasone through inhibiting oxidative stress and mPTP opening

  • Wen-xiao Sun
  • Hai-ya Zheng
  • Jun LanEmail author
Article

Abstract

Existing evidences have emphasized an important role of oxidative stress in dexamethasone (Dex)-induced osteoblastic cell damages. Here, we investigated the possible anti-Dex activity of edaravone in osteoblastic cells, and studied the underlying mechanisms. We showed that edaravone dose-dependently attenuated Dex-induced death and apoptosis of established human or murine osteoblastic cells. Further, Dex-mediated damages to primary murine osteoblasts were also alleviated by edaravone. In osteoblastic cells/osteoblasts, Dex induced significant oxidative stresses, tested by increased levels of reactive oxygen species and lipid peroxidation, which were remarkably inhibited by edaravone. Meanwhile, edaravone repressed Dex-induced mitochondrial permeability transition pore (mPTP) opening, or mitochondrial membrane potential reduction, in osteoblastic cells/osteoblasts. Significantly, edaravone-induced osteoblast-protective activity against Dex was alleviated with mPTP inhibition through cyclosporin A or cyclophilin-D siRNA. Together, we demonstrate that edaravone protects osteoblasts from Dex-induced damages probably through inhibiting oxidative stresses and following mPTP opening.

Keywords

Dexamethasone Osteoblasts Edaravone Oxidative stress Osteonecrosis 

Notes

Acknowledgments

This study is supported by the National Natural Science Foundation of China.

Compliance with Ethical Standards

Conflict of interest

No conflict of interests were stated.

References

  1. 1.
    Weinstein RS (2011) Clinical practice. Glucocorticoid-induced bone disease. N Engl J Med 365:62–70CrossRefPubMedGoogle Scholar
  2. 2.
    Dempster DW (1989) Bone histomorphometry in glucocorticoid-induced osteoporosis. J Bone Miner Res 4:137–141CrossRefPubMedGoogle Scholar
  3. 3.
    Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104:439–446PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Kerachian MA, Seguin C, Harvey EJ (2009) Glucocorticoids in osteonecrosis of the femoral head: a new understanding of the mechanisms of action. J Steroid Biochem Mol Biol 114:121–128CrossRefPubMedGoogle Scholar
  5. 5.
    Mont MA, Jones LC, Hungerford DS (2006) Nontraumatic osteonecrosis of the femoral head: ten years later. J Bone Joint Surg Am 88:1117–1132CrossRefPubMedGoogle Scholar
  6. 6.
    O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA, Manolagas SC, Weinstein RS (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841CrossRefPubMedGoogle Scholar
  7. 7.
    Sato AY, Tu X, McAndrews KA, Plotkin LI, Bellido T (2015) Prevention of glucocorticoid induced-apoptosis of osteoblasts and osteocytes by protecting against endoplasmic reticulum (ER) stress in vitro and in vivo in female mice. Bone 73C:60–68CrossRefGoogle Scholar
  8. 8.
    Plotkin LI, Manolagas SC, Bellido T (2007) Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem 282:24120–24130CrossRefPubMedGoogle Scholar
  9. 9.
    Almeida M, Han L, Ambrogini E, Weinstein RS, Manolagas SC (2011) Glucocorticoids and tumor necrosis factor alpha increase oxidative stress and suppress Wnt protein signaling in osteoblasts. J Biol Chem 286:44326–44335PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    She C, Zhu LQ, Zhen YF, Wang XD, Dong QR (2014) Activation of AMPK protects against hydrogen peroxide-induced osteoblast apoptosis through autophagy induction and NADPH maintenance: new implications for osteonecrosis treatment? Cell Signal 26:1–8CrossRefPubMedGoogle Scholar
  11. 11.
    Yang M, Huang Y, Chen J, Chen YL, Ma JJ, Shi PH (2014) Activation of AMPK participates hydrogen sulfide-induced cyto-protective effect against dexamethasone in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun 454:42–47CrossRefPubMedGoogle Scholar
  12. 12.
    Ding H, Wang T, Xu D, Cha B, Liu J, Li Y (2015) Dexamethasone-induced apoptosis of osteocytic and osteoblastic cells is mediated by TAK1 activation. Biochem Biophys Res Commun 460(2):157–163CrossRefPubMedGoogle Scholar
  13. 13.
    Zhen YF, Wang GD, Zhu LQ, Tan SP, Zhang FY, Zhou XZ, Wang XD (2014) P53 dependent mitochondrial permeability transition pore opening is required for dexamethasone-induced death of osteoblasts. J Cell Physiol 229:1475–1483CrossRefPubMedGoogle Scholar
  14. 14.
    Kikuchi K, Uchikado H, Miyagi N, Morimoto Y, Ito T, Tancharoen S, Miura N, Miyata K, Sakamoto R, Kikuchi C, Iida N, Shiomi N, Kuramoto T, Kawahara K (2011) Beyond neurological disease: new targets for edaravone (Review). Int J Mol Med 28:899–906PubMedGoogle Scholar
  15. 15.
    Kikuchi K, Tancharoen S, Takeshige N, Yoshitomi M, Morioka M, Murai Y, Tanaka E (2013) The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci 14:13909–13930PubMedCentralCrossRefPubMedGoogle Scholar
  16. 16.
    Kikuchi K, Takeshige N, Miura N, Morimoto Y, Ito T, Tancharoen S, Miyata K, Kikuchi C, Iida N, Uchikado H, Miyagi N, Shiomi N, Kuramoto T, Maruyama I, Morioka M, Kawahara KI (2012) Beyond free radical scavenging: beneficial effects of edaravone (Radicut) in various diseases (Review). Exp Ther Med 3:3–8PubMedCentralPubMedGoogle Scholar
  17. 17.
    Feng S, Yang Q, Liu M, Li W, Yuan W, Zhang S, Wu B, Li J (2011) Edaravone for acute ischaemic stroke. Cochrane Database Syst Rev 1:427–433Google Scholar
  18. 18.
    Zhang N, Komine-Kobayashi M, Tanaka R, Liu M, Mizuno Y, Urabe T (2005) Edaravone reduces early accumulation of oxidative products and sequential inflammatory responses after transient focal ischemia in mice brain. Stroke 36:2220–2225CrossRefPubMedGoogle Scholar
  19. 19.
    Edaravone Acute Infarction Study Group (2003) Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc Dis 15:222–229CrossRefGoogle Scholar
  20. 20.
    Wu CH, Cao C, Kim JH, Hsu CH, Wanebo HJ, Bowen WD, Xu J, Marshall J (2012) Trojan-horse nanotube on-command intracellular drug delivery. Nano Lett 12:5475–5480PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Prantner D, Perkins DJ, Lai W, Williams MS, Sharma S, Fitzgerald KA, Vogel SN (2012) 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J Biol Chem 287:39776–39788PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Cortizo AM, Bruzzone L, Molinuevo S, Etcheverry SB (2000) A possible role of oxidative stress in the vanadium-induced cytotoxicity in the MC3T3E1 osteoblast and UMR106 osteosarcoma cell lines. Toxicology 147:89–99CrossRefPubMedGoogle Scholar
  23. 23.
    Fatokun AA, Tome M, Smith RA, Darlington LG, Stone TW (2014) Protection by the flavonoids quercetin and luteolin against peroxide- or menadione-induced oxidative stress in MC3T3-E1 osteoblast cells. Nat Prod Res 29:1–6Google Scholar
  24. 24.
    Fu J, Wang P, Zhang X, Ju S, Li J, Li B, Yu S, Zhang J (2010) Myeloma cells inhibit osteogenic differentiation of mesenchymal stem cells and kill osteoblasts via TRAIL-induced apoptosis. Arch Med Sci 6:496–504PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Inkielewicz-Stepniak I, Radomski MW, Wozniak M (2012) Fisetin prevents fluoride- and dexamethasone-induced oxidative damage in osteoblast and hippocampal cells. Food Chem Toxicol 50:583–589CrossRefPubMedGoogle Scholar
  26. 26.
    Halestrap AP, McStay GP, Clarke SJ (2002) The permeability transition pore complex: another view. Biochimie 84:153–166CrossRefPubMedGoogle Scholar
  27. 27.
    Halestrap AP (2006) Calcium, mitochondria and reperfusion injury: a pore way to die. Biochem Soc Trans 34:232–237CrossRefPubMedGoogle Scholar
  28. 28.
    Javadov S, Kuznetsov A (2013) Mitochondrial permeability transition and cell death: the role of cyclophilin D. Front Physiol 4:76PubMedCentralPubMedGoogle Scholar
  29. 29.
    Hausenloy DJ, Lim SY, Ong SG, Davidson SM, Yellon DM (2010) Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning. Cardiovasc Res 88:67–74PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Woodfield K, Ruck A, Brdiczka D, Halestrap AP (1998) Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J 336(Pt 2):287–290PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Crompton M, Virji S, Ward JM (1998) Cyclophilin-D binds strongly to complexes of the voltage-dependent anion channel and the adenine nucleotide translocase to form the permeability transition pore. Eur J Biochem 258:729–735CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Department of Orthopedic and Hand Surgery, Liyuan HospitalHuazhong University of Science and TechnologyWuhanChina
  2. 2.Department of Clinical LaboratoryThe People’s Hospital of LishuiLishuiChina
  3. 3.Department of OrthopaedicsThe People’s Hospital of LishuiLishuiChina

Personalised recommendations