Skip to main content
Log in

PI3K/Akt and caspase pathways mediate oxidative stress-induced chondrocyte apoptosis

  • Original Paper
  • Published:
Cell Stress and Chaperones Aims and scope

Abstract

Chondrocyte apoptosis is closely related to the development and progression of osteoarthritis (OA); however, the underlying mechanisms remain enigmatic. Previous studies have confirmed that cell apoptosis is one of the main pathological alterations during oxidative stress, and chondrocyte apoptosis induced by oxidative stress plays an important role in the development of OA. Rat chondrocytes exposed to hydrogen peroxide (H2O2) were used as the experimental oxidative stress model. We assessed cell viability, cell apoptosis, levels of intracellular reactive oxygen species (ROS), nitric oxide (NO) production, gene relative expression level of inducible nitric oxide synthase (iNOS), and expressions of iNOS, PI3K, phospho-Akt, caspase-9, and caspase-3. With the rising of intracellular ROS and increasing iNOS synthesis, producing a large amount of NO in chondrocytes, H2O2 decreased the cell viability and induced cell apoptosis of chondrocytes. Furthermore, the levels of caspase-9 and caspase-3 protein expression were significantly elevated as well as the level of p-Akt protein expression when induced by oxidative stress. These findings suggest that oxidative stress-induced chondrocyte apoptosis occurred via activating both PI3K/Akt and caspase pathways in the early stage in these processes.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Berenbaum F (2008) New horizons and perspectives in the treatment of osteoarthritis. Arthritis Res Ther 10(Suppl 2):S1

    Article  Google Scholar 

  • Betteridge N (2003) Bone and joint diseases around the world. Arthritis--the greatest health, disability, and civil rights challenge: a UK and international perspective. J Rheumatol Suppl 67:36–37

    PubMed  Google Scholar 

  • Brandl A, Hartmann A, Bechmann V, Graf B, Nerlich M, Angele P (2011) Oxidative stress induces senescence in chondrocytes. J Orthop Res 29:1114–1120

    Article  CAS  Google Scholar 

  • Carmody RJ, Cotter TG (2000) Oxidative stress induces caspase-independent retinal apoptosis in vitro. Cell Death Differ 7:282–291

    Article  CAS  Google Scholar 

  • Carvour M, Song C, Kaul S, Anantharam V, Kanthasamy A, Kanthasamy A (2008) Chronic low-dose oxidative stress induces caspase-3-dependent PKCdelta proteolytic activation and apoptosis in a cell culture model of dopaminergic neurodegeneration. Ann N Y Acad Sci 1139:197–205

    Article  CAS  Google Scholar 

  • Dai P, Mao Y, Sun X, Li X, Muhammad I, Gu W, Zhang D, Zhou Y, Ma J, Ni Z, Huang S (2017) Attenuation of oxidative stress-induced osteoblast apoptosis by curcumin is associated with preservation of mitochondrial functions and increased Akt-GSK3beta signaling. Cell Physiol Biochem 41:661–677

    Article  CAS  Google Scholar 

  • Du Z, Li S, Liu L, Yang Q, Zhang H, Gao C (2015) NADPH oxidase 3-associated oxidative stress and caspase 3-dependent apoptosis in the cochleae of D-galactose-induced aged rats. Mol Med Rep 12:7883–7890

    Article  CAS  Google Scholar 

  • Facchini A, Stanic I, Cetrullo S, Borzi RM, Filardo G, Flamigni F (2011) Sulforaphane protects human chondrocytes against cell death induced by various stimuli. J Cell Physiol 226:1771–1779

    Article  CAS  Google Scholar 

  • Faghiri Z, Bazan NG (2010) PI3K/Akt and mTOR/p70S6K pathways mediate neuroprotectin D1-induced retinal pigment epithelial cell survival during oxidative stress-induced apoptosis. Exp Eye Res 90:718–725

    Article  CAS  Google Scholar 

  • Grishko V, Xu M, Ho R, Mates A, Watson S, Kim JT, Wilson GL, Pearsall AWt (2009) Effects of hyaluronic acid on mitochondrial function and mitochondria-driven apoptosis following oxidative stress in human chondrocytes. J Biol Chem 284:9132–9139

    Article  CAS  Google Scholar 

  • Hosseinzadeh A, Bahrampour Juybari K, Fatemi MJ, Kamarul T, Bagheri A, Tekiyehmaroof N, Sharifi AM (2017) Protective effect of ginger (Zingiber officinale roscoe) extract against oxidative stress and mitochondrial apoptosis induced by interleukin-1beta in cultured chondrocytes. Cells Tissues Organs 204:241–250

    Article  CAS  Google Scholar 

  • Hu L, Chen L, Yang G, Li L, Sun H, Chang Y, Tu Q, Wu M, Wang H (2011) HBx sensitizes cells to oxidative stress-induced apoptosis by accelerating the loss of Mcl-1 protein via caspase-3 cascade. Mol Cancer 10:43

    Article  CAS  Google Scholar 

  • Huang J, Cui H, Peng X, Fang J, Zuo Z, Deng J, Wu B (2013) The association between splenocyte apoptosis and alterations of Bax, Bcl-2 and caspase-3 mRNA expression, and oxidative stress induced by dietary nickel chloride in broilers. Int J Environ Res Public Health 10:7310–7326

    Article  Google Scholar 

  • Kang KA, Wang ZH, Zhang R, Piao MJ, Kim KC, Kang SS, Kim YW, Lee J, Park D, Hyun JW (2010) Myricetin protects cells against oxidative stress-induced apoptosis via regulation of PI3K/Akt and MAPK signaling pathways. Int J Mol Sci 11:4348–4360

    Article  CAS  Google Scholar 

  • LaPrade RF, Swiontkowski MF (1999) New horizons in the treatment of osteoarthritis of the knee. JAMA 281:876–878

    Article  CAS  Google Scholar 

  • Li H, Song F, Duan LR, Sheng JJ, Xie YH, Yang Q, Chen Y, Dong QQ, Zhang BL, Wang SW (2016) Paeonol and danshensu combination attenuates apoptosis in myocardial infarcted rats by inhibiting oxidative stress: roles of Nrf2/HO-1 and PI3K/Akt pathway. Sci Rep 6:23693

    Article  CAS  Google Scholar 

  • Maheshwari A, Misro MM, Aggarwal A, Sharma RK, Nandan D (2011) N-acetyl-L-cysteine counteracts oxidative stress and prevents H2O2 induced germ cell apoptosis through down-regulation of caspase-9 and JNK/c-Jun. Mol Reprod Dev 78:69–79

    Article  CAS  Google Scholar 

  • Matheny RW Jr, Adamo ML (2010) PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts. Cell Death Differ 17:677–688

    Article  CAS  Google Scholar 

  • Mendivil-Perez M, Velez-Pardo C, Jimenez-Del-Rio M (2012) TPEN induces apoptosis independently of zinc chelator activity in a model of acute lymphoblastic leukemia and ex vivo acute leukemia cells through oxidative stress and mitochondria caspase-3- and AIF-dependent pathways. Oxidative Med Cell Longev 2012(3):1–14

    Article  Google Scholar 

  • Oliviero F, Ramonda R, Punzi L (2010) New horizons in osteoarthritis. Swiss Med Wkly 140:w13098

    CAS  PubMed  Google Scholar 

  • Palferman TG (2003) Bone and joint diseases around the world. The UK perspective. J Rheumatol Suppl 67:33–35

    PubMed  Google Scholar 

  • Sekar S, Crawford R, Xiao Y, Prasadam I (2017) Dietary fats and osteoarthritis: insights, evidences, and new horizons. J Cell Biochem 118:453–463

    Article  CAS  Google Scholar 

  • Wang Y, Wang W, Qiu E (2017) Protection of oxidative stress induced apoptosis in osteosarcoma cells by dihydromyricetin through down-regulation of caspase activation and up-regulation of BcL-2. Saudi J Biol Sci 24:837–842

    Article  CAS  Google Scholar 

  • Xu J, Qian J, Xie X, Lin L, Zou Y, Fu M, Huang Z, Zhang G, Su Y, Ge J (2012) High density lipoprotein protects mesenchymal stem cells from oxidative stress-induced apoptosis via activation of the PI3K/Akt pathway and suppression of reactive oxygen species. Int J Mol Sci 13:17104–17120

    Article  CAS  Google Scholar 

  • Yan X, Wu H, Wu Z, Hua F, Liang D, Sun H, Yang Y, Huang D, Bian JS (2017) The new synthetic H2S-releasing SDSS protects MC3T3-E1 osteoblasts against H2O2-induced apoptosis by suppressing oxidative stress, inhibiting MAPKs, and activating the PI3K/Akt pathway. Front Pharmacol 8:07

    PubMed  PubMed Central  Google Scholar 

  • Yang K, Zhang H, Luo Y, Zhang J, Wang M, Liao P, Cao L, Guo P, Sun G, Sun X (2017) Gypenoside XVII prevents atherosclerosis by attenuating endothelial apoptosis and oxidative stress: insight into the ERalpha-mediated PI3K/Akt pathway. Int J Mol Sci 18

  • Yao H, Tang X, Shao X, Feng L, Wu N, Yao K (2007) Parthenolide protects human lens epithelial cells from oxidative stress-induced apoptosis via inhibition of activation of caspase-3 and caspase-9. Cell Res 17:565–571

    Article  CAS  Google Scholar 

  • Zhuang C, Wang Y, Zhang Y, Xu N (2018) Oxidative stress in osteoarthritis and antioxidant effect of polysaccharide from angelica sinensis. Int J Biol Macromol 115:281–286

    Article  CAS  Google Scholar 

  • Zhuang C, Xu NW, Gao GM, Ni S, Miao KS, Li CK, Wang LM, Xie HG (2016) Polysaccharide from Angelica sinensis protects chondrocytes from H2O2-induced apoptosis through its antioxidant effects in vitro. Int J Biol Macromol 87:322–328

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Chao Zhuang.

Ethics declarations

This study was reviewed and approved by the ethics committee of the Second People’s Hospital of Changzhou, Jiangsu, China.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, D., Ni, S., Miao, KS. et al. PI3K/Akt and caspase pathways mediate oxidative stress-induced chondrocyte apoptosis. Cell Stress and Chaperones 24, 195–202 (2019). https://doi.org/10.1007/s12192-018-0956-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12192-018-0956-4

Keywords

Navigation