Skip to main content

Advertisement

SpringerLink
Log in

Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Pro-inflammatory cytokine-induced chondrocyte apoptosis is a primary cause of cartilage destruction in the progression of rheumatoid arthritis (RA). Advanced oxidation protein products (AOPPs), a novel pro-inflammatory mediator, have been confirmed to accumulate in patients with RA. However, the effect of AOPPs accumulation on chondrocyte apoptosis and the associated cellular mechanisms remains unclear. The present study demonstrated that the plasma formation of AOPPs was enhanced in RA rats compared with normal. Then, chondrocyte were treated with AOPPs-modified rat serum albumin (AOPPs-RSA) in vitro. Exposure of chondrocyte to AOPPs activated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased expression of NADPH oxidase subunits, which was mediated by receptor for advanced glycation end products (RAGE), but not scavenger receptor CD36. Moreover, AOPPs challenge triggered NADPH oxidase-dependent ROS generation which induced mitochondrial dysfunction and endoplasmic reticulum stress resulted in activation of caspase family that eventually lead to apoptosis. Lastly, blockade of RAGE, instead of CD36, largely attenuated these signals. Our study demonstrated first time that AOPPs induce chondrocyte apoptosis via RAGE-mediated and redox-dependent intrinsic apoptosis pathway in vitro. These data implicates that AOPPs may represent a novel pathogenic factor that contributes to RA progression. Targeting AOPPs-triggered cellular mechanisms might emerge as a promising therapeutic option for patients with RA.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Abbreviations

RA:

Rheumatoid arthritis

ROS:

Reactive oxygen species

AOPPs:

Advanced oxidation protein products

MPO:

Myeloperoxidase

NADPH:

Nicotinamide adenine dinucleotide phosphate

RAGE:

Receptor for advanced glycation end products

ER:

Endoplasmic reticulum

chop:

C/EBP homologous protein

PARP:

Poly ADP-ribose polymerase

Δψm:

Mitochondrial membrane potential

RSA:

Rat serum albumin

References

  1. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442

    Article  PubMed  CAS  Google Scholar 

  2. Schuerwegh AJ, Dombrecht EJ, Stevens WJ, Van Offel JF, Bridts CH, De Clerck LS (2003) Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis Cartilage 11:681–687

    Article  PubMed  CAS  Google Scholar 

  3. Polzer K, Schett G, Zwerina J (2007) The lonely death: chondrocyte apoptosis in TNF-induced arthritis. Autoimmunity 40:333–336

    Article  PubMed  CAS  Google Scholar 

  4. Lotz M (2001) Cytokines in cartilage injury and repair. Clin Orthop Relat Res 391:S108–S115

    Article  PubMed  Google Scholar 

  5. Wruck CJ, Fragoulis A, Gurzynski A, Brandenburg LO, Kan YW, Chan K, Hassenpflug J, Freitag-Wolf S, Varoga D, Lippross S, Pufe T (2011) Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice. Ann Rheum Dis 70:844–850

    Article  PubMed  CAS  Google Scholar 

  6. Fay J, Varoga D, Wruck CJ, Kurz B, Goldring MB, Pufe T (2006) Reactive oxygen species induce expression of vascular endothelial growth factor in chondrocytes and human articular cartilage explants. Arthritis Res Ther 8:R189

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hitchon CA, El-Gabalawy HS (2004) Oxidation in rheumatoid arthritis. Arthritis Res Ther 6:265–278

    Article  PubMed  PubMed Central  Google Scholar 

  8. De Bandt M, Grossin M, Driss F, Pincemail J, Babin-Chevaye C, Pasquier C (2002) Vitamin E uncouples joint destruction and clinical inflammation in a transgenic mouse model of rheumatoid arthritis. Arthritis Rheum 46:522–532

    Article  PubMed  Google Scholar 

  9. Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? Lancet 344:721–724

    Article  PubMed  CAS  Google Scholar 

  10. Reinheckel T, Nedelev B, Prause J, Augustin W, Schulz HU, Lippert H, Halangk W (1998) Occurrence of oxidatively modified proteins: an early event in experimental acute pancreatitis. Free Radic Biol Med 24:393–400

    Article  PubMed  CAS  Google Scholar 

  11. DeAtley SM, Aksenov MY, Aksenova MV, Carney JM, Butterfield DA (1998) Adriamycin induces protein oxidation in erythrocyte membranes. Pharmacol Toxicol 83:62–68

    Article  PubMed  CAS  Google Scholar 

  12. Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B (1996) Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 49:1304–1313

    Article  PubMed  CAS  Google Scholar 

  13. Stamp LK, Khalilova I, Tarr JM, Senthilmohan R, Turner R, Haigh RC, Winyard PG, Kettle AJ (2012) Myeloperoxidase and oxidative stress in rheumatoid arthritis. Rheumatology (Oxford) 51:1796–1803

    Article  CAS  Google Scholar 

  14. Baskol G, Demir H, Baskol M, Kilic E, Ates F, Karakukcu C, Ustdal M (2006) Investigation of protein oxidation and lipid peroxidation in patients with rheumatoid arthritis. Cell Biochem Funct 24:307–311

    Article  PubMed  CAS  Google Scholar 

  15. Cao W, Xu J, Zhou ZM, Wang GB, Hou FF, Nie J (2013) Advanced oxidation protein products activate intrarenal renin-angiotensin system via a CD36-mediated, redox-dependent pathway. Antioxid Redox Signal 18:19–35

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Zhou LL, Hou FF, Wang GB, Yang F, Xie D, Wang YP, Tian JW (2009) Accumulation of advanced oxidation protein products induces podocyte apoptosis and deletion through NADPH-dependent mechanisms. Kidney Int 76:1148–1160

    Article  PubMed  Google Scholar 

  17. Guo ZJ, Niu HX, Hou FF, Zhang L, Fu N, Nagai R, Lu X, Chen BH, Shan YX, Tian JW, Nagaraj RH, Xie D, Zhang X (2008) Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal 10:1699–1712

    Article  PubMed  CAS  Google Scholar 

  18. Xie F, Sun S, Xu A, Zheng S, Xue M, Wu P, Zeng JH, Bai L (2014) Advanced oxidation protein products induce intestine epithelial cell death through a redox-dependent, c-jun N-terminal kinase and poly (ADP-ribose) polymerase-1-mediated pathway. Cell Death Dis 5:e1006

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Zheng S, Zhong ZM, Qin S, Chen GX, Wu Q, Zeng JH, Ye WB, Li W, Yuan K, Yao L, Chen JT (2013) Advanced oxidation protein products induce inflammatory response in fibroblast-like synoviocytes through NADPH oxidase -dependent activation of NF-kappaB. Cell Physiol Biochem 32:972–985

    Article  PubMed  CAS  Google Scholar 

  20. Zhong ZM, Bai L, Chen JT (2009) Advanced oxidation protein products inhibit proliferation and differentiation of rat osteoblast-like cells via NF-kappaB pathway. Cell Physiol Biochem 24:105–114

    Article  PubMed  CAS  Google Scholar 

  21. Zhou LL, Cao W, Xie C, Tian J, Zhou Z, Zhou Q, Zhu P, Li A, Liu Y, Miyata T, Hou FF, Nie J (2012) The receptor of advanced glycation end products plays a central role in advanced oxidation protein products-induced podocyte apoptosis. Kidney Int 82:759–770

    Article  PubMed  CAS  Google Scholar 

  22. Takahashi T, Katsuta S, Tamura Y, Nagase N, Suzuki K, Nomura M, Tomatsu S, Miyamoto K, Kobayashi S (2013) Bone-targeting endogenous secretory receptor for advanced glycation end products rescues rheumatoid arthritis. Mol Med 19:183–194

    Article  PubMed  PubMed Central  Google Scholar 

  23. Valente AJ, Yoshida T, Clark RA, Delafontaine P, Siebenlist U, Chandrasekar B (2013) Advanced oxidation protein products induce cardiomyocyte death via Nox2/Rac1/superoxide-dependent TRAF3IP2/JNK signaling. Free Radic Biol Med 60:125–135

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Wu Q, Zhong ZM, Pan Y, Zeng JH, Zheng S, Zhu SY, Chen JT (2015) Advanced oxidation protein products as a novel marker of oxidative stress in postmenopausal osteoporosis. Med Sci Monit 21:2428–2432

    Article  PubMed  PubMed Central  Google Scholar 

  25. Opolka A, Straub RH, Pasoldt A, Grifka J, Grassel S (2012) Substance P and norepinephrine modulate murine chondrocyte proliferation and apoptosis. Arthritis Rheum 64:729–739

    Article  PubMed  CAS  Google Scholar 

  26. Yang X, Teguh D, Wu JP, He B, Kirk TB, Qin S, Li S, Chen H, Xue W, Ng B, Chim SM, Tickner J, Xu J (2015) Protein kinase C delta null mice exhibit structural alterations in articular surface, intra-articular and subchondral compartments. Arthritis Res Ther 17:210

    Article  PubMed  PubMed Central  Google Scholar 

  27. Zhong ZM, Li T, Xu ZX, Meng TT, Zeng JH, Zheng S, Ye WB, Wu Q, Chen JT (2013) Effect of melatonin on the proliferation and differentiation of chondrocytes from rat vertebral body growth plate in vitro. Int J Med Sci 10:1392–1398

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kuhn K, D’Lima DD, Hashimoto S, Lotz M (2004) Cell death in cartilage. Osteoarthritis Cartilage 12:1–16

    Article  PubMed  CAS  Google Scholar 

  29. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423:356–361

    Article  PubMed  CAS  Google Scholar 

  30. Yu H, Ye WB, Zhong ZM, Ding RT, Chen JT (2015) Effect of advanced oxidation protein products on articular cartilage and synovium in a rabbit osteoarthritis model. Orthop Surg 7:161–167

    Article  PubMed  Google Scholar 

  31. Adan N, Guzman-Morales J, Ledesma-Colunga MG, Perales-Canales SI, Quintanar-Stephano A, Lopez-Barrera F, Mendez I, Moreno-Carranza B, Triebel J, Binart N, Martinez DLEG, Thebault S, Clapp C (2013) Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis. J Clin Invest 123:3902–3913

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Uehara Y, Hirose J, Yamabe S, Okamoto N, Okada T, Oyadomari S, Mizuta H (2014) Endoplasmic reticulum stress-induced apoptosis contributes to articular cartilage degeneration via C/EBP homologous protein. Osteoarthritis Cartilage 22:1007–1017

    Article  PubMed  CAS  Google Scholar 

  33. Reed KN, Wilson G, Pearsall A, Grishko VI (2014) The role of mitochondrial reactive oxygen species in cartilage matrix destruction. Mol Cell Biochem 397:195–201

    Article  PubMed  CAS  Google Scholar 

  34. Vignais PV (2002) The superoxide-generating NADPH oxidase: structural aspects and activation mechanism. Cell Mol Life Sci 59:1428–1459

    Article  PubMed  CAS  Google Scholar 

  35. Kleniewska P, Piechota A, Skibska B, Goraca A (2012) The NADPH oxidase family and its inhibitors. Arch Immunol Ther Exp (Warsz) 60:277–294

    Article  CAS  Google Scholar 

  36. Joshi S, Peck AB, Khan SR (2013) NADPH oxidase as a therapeutic target for oxalate induced injury in kidneys. Oxid Med Cell Longev 2013:462361

    Article  PubMed  PubMed Central  Google Scholar 

  37. Tam LS, Shang Q, Li EK, Wong S, Li RJ, Lee KL, Leung YY, Ying KY, Yim CW, Kun EW, Leung MH, Li M, Li TK, Zhu TY, Chui RK, Tseung L, Yu SL, Kuan WP, Yu CM (2013) Serum soluble receptor for advanced glycation end products levels and aortic augmentation index in early rheumatoid arthritis–a prospective study. Semin Arthritis Rheum 42:333–345

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81272042 and No. 81472135) and the Natural Science Foundation of Guangdong Province (No. S2012010008875, No. S2012040006830 and No. 2015A030310481) and in part by the Scientific Research Initiative of Southern Medical University (No. PY2014N038).

Author information

Author notes

    Authors and Affiliations

    1. Department of Spinal Surgery, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, China

      Qian Wu, Zhao-Ming Zhong, Si-Yuan Zhu, Cong-Rui Liao, Shuai Zheng, Ruo-Ting Ding, Qing Ye, Wen-Bin Ye, Wei Li & Jian-Ting Chen

    2. Department of Oncology, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, China

      Ying Pan

    3. Department of Orthopedics, Jiangxi Provincial People’s Hospital, Nanchang, China

      Ji-Huan Zeng

    4. Department of Orthopedics, Shekou People’s Hospital, Shenzhen, China

      Qing-Song Lin

    Authors
    1. Qian Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Zhao-Ming Zhong
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Si-Yuan Zhu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Cong-Rui Liao
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ying Pan
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Ji-Huan Zeng
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Shuai Zheng
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Ruo-Ting Ding
      View author publications

      You can also search for this author in PubMed Google Scholar

    9. Qing-Song Lin
      View author publications

      You can also search for this author in PubMed Google Scholar

    10. Qing Ye
      View author publications

      You can also search for this author in PubMed Google Scholar

    11. Wen-Bin Ye
      View author publications

      You can also search for this author in PubMed Google Scholar

    12. Wei Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    13. Jian-Ting Chen
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jian-Ting Chen.

    Ethics declarations

    Conflict of interest

    The authors declare that they have no conflict of interests.

    Additional information

    Qian Wu and Zhao-Ming Zhong have contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Wu, Q., Zhong, ZM., Zhu, SY. et al. Advanced oxidation protein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway. Apoptosis 21, 36–50 (2016). https://doi.org/10.1007/s10495-015-1191-4

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10495-015-1191-4

    Keywords

    Search

    Navigation