Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis

  • Authors:
    • Koji Takada
    • Jun Hirose
    • Soichiro Yamabe
    • Yushuke Uehara
    • Hiroshi Mizuta
  • View Affiliations

  • Published online on: January 3, 2013     https://doi.org/10.3892/br.2013.52
  • Pages: 315-319
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Nitric oxide (NO) is one of the most important mediators of chondrocyte apoptosis, which is a notable feature of cartilage degeneration. While apoptosis of chondrocytes is induced by p53, NO can also induce endoplasmic reticulum (ER) stress, which may be involved in the process of NO-induced chondrocyte apoptosis. The aims of this study were to determine whether NO-induced ER stress (ERS) leads to apoptosis of chondrocytes and to investigate the temporal relationship between the expression of C/EBP-homologous protein (CHOP), an ERS-associated apoptotic molecule, and the expression of p53 during apoptosis in NO‑stimulated chondrocytes. Rat chondrocytes were stimulated by sodium nitroprusside (SNP), a NO donor. Real-time polymerase chain reaction (PCR) was performed to analyze the mRNA expression of CHOP, glucose-regulated protein (GRP78) and p53. Apoptosis of chondrocytes was quantified using an enzyme-linked immunosorbent assay (ELISA). SNP‑treated chondrocytes showed an increase in CHOP and GRP78 mRNA expression and underwent apoptosis. Sodium 4-phenylbutyrate (PBA), an ERS inhibitor, reduced CHOP and GRP78, as well as SNP‑stimulated apoptosis of chondrocytes, without affecting the SNP-dependent generation of NO. In addition, the blockade of CHOP following siRNA transfection reduced SNP‑induced apoptosis of chondrocytes. The CHOP expression increased after apoptosis was detected in the SNP-treated chondrocytes, whereas the p53 expression increased prior to apoptosis. These data demonstrated that NO-induced ERS leads chondrocytes to apoptosis, although this effect appears to be limited to persistent impairment of NO stimulation. These findings may provide insight into the pathology of cartilage degeneration.

References

1 

Blanco FJ, Ochs RL, Schwarz H and Lotz M: Chondrocyte apoptosis induced by nitric oxide. Am J Pathol. 146:75–85. 1995.PubMed/NCBI

2 

Hashimoto S, Takahashi K, Amiel D, Coutts RD and Lotz M: Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum. 41:1266–1274. 1998. View Article : Google Scholar : PubMed/NCBI

3 

Pelletier JP, Jovanovic DV, Lascau-Coman V, Fernandes JC, Manning PT, Connor JR, Currie MG and Martel-Pelletier J: Selective inhibition of inducible nitric oxide synthase reduces progression of experimental osteoarthritis in vivo: possible link with the reduction in chondrocyte apoptosis and caspase 3 level. Arthritis Rheum. 43:1290–1299. 2000. View Article : Google Scholar

4 

Kim SJ, Hwang SG, Shin DY, Kang SS and Chun JS: p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation. J Biol Chem. 277:33501–33508. 2002. View Article : Google Scholar : PubMed/NCBI

5 

Kim SJ, Ju JW, Oh CD, Yoon YM, Song WK, Kim JH, Yoo YJ, Bang OS, Kang SS and Chun JS: ERK-1/2 and p38 kinase oppositely regulate nitric oxide-induced apoptosis of chondrocytes in association with p53, caspase-3, and differentiation status. J Biol Chem. 277:1332–1339. 2002. View Article : Google Scholar : PubMed/NCBI

6 

Ron D and Walter P: Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 8:519–529. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Gotoh T and Mori M: Nitric oxide and endoplasmic reticulum stress. Arterioscler Thromb Vasc Biol. 26:1439–1446. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Horton WE Jr, Bennion P and Yang L: Cellular, molecular, and matrix changes in cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact. 6:379–381. 2006.PubMed/NCBI

9 

Nugent AE, Speicher DM, Gradisar I, McBurney DL, Baraga A, Doane KJ and Horton WE Jr: Advanced osteoarthritis in humans is associated with altered collagen VI expression and upregulation of ER-stress markers Grp78 and bag-1. J Histochem Cytochem. 57:923–931. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Yang L, Carlson SG, McBurney D and Horton WE Jr: Multiple signals induce endoplasmic reticulum stress in both primary and immortalized chondrocytes resulting in loss of differentiation, impaired cell growth, and apoptosis. J Biol Chem. 280:31156–31165. 2005. View Article : Google Scholar

11 

Takada K, Hirose J, Senba K, Yamabe S, Oike Y, Gotoh T and Mizuta H: Enhanced apoptotic and reduced protective response in chondrocytes following endoplasmic reticulum stress in osteoarthritic cartilage. Int J Exp Pathol. 92:232–242. 2011. View Article : Google Scholar

12 

Oliver BL, Cronin CG, Zhang-Benoit Y, Goldring MB and Tanzer ML: Divergent stress responses to IL-1beta, nitric oxide, and tunicamycin by chondrocytes. J Cell Physiol. 204:45–50. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Hirose J, Ryan LM and Masuda I: Up-regulated expression of cartilage intermediate-layer protein and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease. Arthritis Rheum. 46:3218–3229. 2002. View Article : Google Scholar

14 

Burrows JA, Willis LK and Perlmutter DH: Chemical chaperones mediate increased secretion of mutant alpha 1-antitrypsin (alpha 1-AT) Z: a potential pharmacological strategy for prevention of liver injury and emphysema in alpha 1-AT deficiency. Proc Natl Acad Sci USA. 97:1796–1801. 2000. View Article : Google Scholar

15 

Kubota K, Niinuma Y, Kaneko M, Okuma Y, Sugai M, Omura T, Uesugi M, Uehara T, Hosoi T and Nomura Y: Suppressive effects of 4-phenylbutyrate on the aggregation of Pael receptors and endoplasmic reticulum stress. J Neurochem. 97:1259–1268. 2006. View Article : Google Scholar : PubMed/NCBI

16 

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH and Hotamisligil GS: Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science. 306:457–461. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Qi X, Hosoi T, Okuma Y, Kaneko M and Nomura Y: Sodium 4-phenylbutyrate protects against cerebral ischemic injury. Mol Pharmacol. 66:899–908. 2004. View Article : Google Scholar : PubMed/NCBI

18 

Qu L, Huang S, Baltzis D, Rivas-Estilla AM, Pluquet O, Hatzoglou M, Koumenis C, Taya Y, Yoshimura A and Koromilas AE: Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev. 18:261–277. 2004. View Article : Google Scholar : PubMed/NCBI

19 

Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E and Mori M: Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA. 98:10845–10850. 2001. View Article : Google Scholar : PubMed/NCBI

20 

Gotoh T, Oyadomari S, Mori K and Mori M: Nitric oxide-induced apoptosis in RAW 264.7 macrophages is mediated by endoplasmic reticulum stress pathway involving ATF6 and CHOP. J Biol Chem. 277:12343–12350. 2002. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

March 2013
Volume 1 Issue 2

Print ISSN: 2049-9434
Online ISSN:2049-9442

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Takada, K., Hirose, J., Yamabe, S., Uehara, Y., & Mizuta, H. (2013). Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis. Biomedical Reports, 1, 315-319. https://doi.org/10.3892/br.2013.52
MLA
Takada, K., Hirose, J., Yamabe, S., Uehara, Y., Mizuta, H."Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis". Biomedical Reports 1.2 (2013): 315-319.
Chicago
Takada, K., Hirose, J., Yamabe, S., Uehara, Y., Mizuta, H."Endoplasmic reticulum stress mediates nitric oxide-induced chondrocyte apoptosis". Biomedical Reports 1, no. 2 (2013): 315-319. https://doi.org/10.3892/br.2013.52