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Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis

  • Original Research Paper
  • Published:
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Abstract

Objective

Defective apoptosis contributes to the massive synovial hyperplasia in rheumatoid arthritis (RA), but the mechanism is largely unknown. To investigate the reasons for the reduced apoptosis in RA synovium, we analyzed autophagy and its relationship to apoptosis in synovial tissues from RA and osteoarthritis (OA) patients.

Methods

Synovial tissues were obtained from seven RA and 12 OA patients undergoing knee replacement surgery. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and staining for p85 fragment of PolyADP-ribose polymerase (PARP). Autophagy was determined by immunoblotting for the autophagic markers Beclin-1 and LC3. MicroRNA-30a (miR-30a), which targets Beclin-1, was measured by real-time RT-PCR. The interplay between autophagy and apoptosis was determined via Spearman’s correlation analysis.

Results

In comparison with OA, the synovial tissues from RA displayed decreased TUNEL-positive nuclei (P < 0.01). In contrast, Beclin-1 and LC3 were overexpressed in the synovial lining layers of RA, which was correlated with decreased levels of miR-30a. Moreover, there was a significant reverse relationship between apoptosis and autophagy in RA synovial tissues (P < 0.01 and r = −0.8937).

Conclusion

The impaired apoptosis in RA synovium might result from increased autophagy, which in turn could be due to the deregulation of miRNA-30a.

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Abbreviations

H&E:

Hematoxylin–eosin

OA:

Osteoarthritis

OD:

Optical density

PARP:

PolyADP-ribose polymerase

RA:

Rheumatoid arthritis

SF:

Synovial fibroblast

TBST:

Tris-buffered saline with Tween 20

TUNEL:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling

References

  1. Andersson AK, Li C, Brennan FM. Recent developments in the immunobiology of rheumatoid arthritis. Arthritis Res Ther. 2008;10:204–12.

    Article  PubMed  Google Scholar 

  2. Humby F, Manzo A, Kirkham B, Pitzalis C. The synovial membrane as a prognostic tool in rheumatoid arthritis. Autoimmun Rev. 2007;6:248–52.

    Article  PubMed  Google Scholar 

  3. Korb A, Pavenstadt H, Pap T. Cell death in rheumatoid arthritis. Apoptosis. 2009;14:447–54.

    Article  PubMed  Google Scholar 

  4. Wachsmann D, Sibilia J. Survival in the rheumatoid synovium. Joint Bone Spine. 2011;78:435–7.

    Article  PubMed  Google Scholar 

  5. Meinecke I, Cinski A, Baier A, Peters MA, Dankbar B, Wille A, et al. Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc Natl Acad Sci USA. 2007;104:5073–8.

    Article  PubMed  CAS  Google Scholar 

  6. Perlman H, Liu H, Georganas C, Koch AE, Shamiyeh E, Haines GK 3rd, et al. Differential expression pattern of the antiapoptotic proteins, Bcl-2 and FLIP, in experimental arthritis. Arthritis Rheum. 2001;44:2899–908.

    Article  PubMed  CAS  Google Scholar 

  7. Bai SC, Liu HT, Chen KH, Eksarko P, Perlman H, Moore TL, et al. NF-kappa B-regulated expression of cellular FLIP protects rheumatoid arthritis synovial fibroblasts from tumor necrosis factor alpha-mediated apoptosis. Arthritis Rheum. 2004;50:3844–55.

    Article  PubMed  CAS  Google Scholar 

  8. Drynda A, Quax PHA, Neumann M, van der Laan WH, Pap G, Drynda S, et al. Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha on fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. J Immunol. 2005;174:6524–31.

    PubMed  CAS  Google Scholar 

  9. Dharmapatni AASSK, Smith MD, Findlay DM, Holding CA, Evdokiou A, Ahern MJ, et al. Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium. Arthritis Res Ther. 2009;11(1):R13.

    Article  PubMed  Google Scholar 

  10. Schwarten M, Mohrluder J, Ma PX, Stoldt M, Thielmann Y, Stangler T, et al. Nix directly binds to GABARAP A possible crosstalk between apoptosis and autophagy. Autophagy. 2009;5:690–8.

    Article  PubMed  CAS  Google Scholar 

  11. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A. Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ. 2009;16:966–75.

    Article  PubMed  CAS  Google Scholar 

  12. Vellai T. Autophagy genes and ageing. Cell Death Differ. 2009;16:94–102.

    Article  PubMed  CAS  Google Scholar 

  13. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132:27–42.

    Article  PubMed  CAS  Google Scholar 

  14. Cecconi F, Levine B. The role of autophagy in mammalian development: cell makeover rather than cell death. Dev Cell. 2008;15:344–57.

    Article  PubMed  CAS  Google Scholar 

  15. Sperandio S, de Belle I, Bredesen DE. An alternative, nonapoptotic form of programmed cell death. Proc Natl Acad Sci USA. 2000;97:14376–81.

    Article  PubMed  CAS  Google Scholar 

  16. Kraft LJ, Kenworthy AK. Imaging protein complex formation in the autophagy pathway: analysis of the interaction of LC3 and Atg4B(C74A) in live cells using Forster resonance energy transfer and fluorescence recovery after photobleaching. J Biomed Opt. 2012;17:011008.

    Article  PubMed  Google Scholar 

  17. Vazquez CL, Colombo MI. Beclin 1 modulates the anti-apoptotic activity of Bcl-2 Insights from a pathogen infection system. Autophagy. 2010;6:177–8.

    Article  PubMed  Google Scholar 

  18. Furuya N, Yu F, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46–52.

    Article  PubMed  CAS  Google Scholar 

  19. Kirkin V, McEwan DG, Novak I, Dikic I. A role for ubiquitin in selective autophagy. Mol Cell. 2009;34:259–69.

    Article  PubMed  CAS  Google Scholar 

  20. Kuma A, Matsui M, Mizushima N. LC3, an autophagosome marker, can be incorporated into protein aggregates independent of autophagy. Autophagy. 2007;3:323–8.

    PubMed  CAS  Google Scholar 

  21. Shin YJ, Han SH, Kim DS, Lee GH, Yoo WH, Kang YM, et al. Autophagy induction and CHOP under-expression promotes survival of fibroblasts from rheumatoid arthritis patients under endoplasmic reticulum stress. Arthritis Res Ther. 2010;12:R19.

    Article  PubMed  Google Scholar 

  22. Fassbender HG. Histomorphological basis of articular-cartilage destruction in rheumatoid-arthritis. Coll Relat Res. 1983;3:141–55.

    Article  PubMed  CAS  Google Scholar 

  23. MullerLadner U, Kriegsmann J, Franklin BN, Matsumoto S, Geiler T, Gay RE, et al. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol. 1996;149:1607–15.

    CAS  Google Scholar 

  24. Muller-Ladner U, Ospelt C, Gay S, Distler O, Pap T. Cells of the synovium in rheumatoid arthritis—synovial fibroblasts. Arthritis Res Ther. 2007;9:223–32.

    Article  PubMed  Google Scholar 

  25. Zhu H, Wu H, Liu XP, Li BA, Chen Y, Ren XC, et al. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy. 2009;5:816–23.

    PubMed  CAS  Google Scholar 

  26. Chen ZK, Wang LH. Expression of PDCD5 gene in synovium of rheumatoid arthritis. Chin J Rheumatol. 2008;1:36–9.

    Google Scholar 

  27. Pap T, Franz JK, Hummel KM, Jeisy E, Gay R, Gay S. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res. 2000;2:59–64.

    Article  PubMed  CAS  Google Scholar 

  28. Karantza-Wadsworth V, Patel S, Kravchuk O, Chen GH, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21:1621–35.

    Article  PubMed  CAS  Google Scholar 

  29. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 2007;21:1367–81.

    Article  PubMed  CAS  Google Scholar 

  30. Smith MD, Weedon H, Papangelis V, Walker J, Roberts-Thomson PJ, Ahern MJ. Apoptosis in the rheumatoid arthritis synovial membrane: modulation by disease-modifying anti-rheumatic drug treatment. Rheumatology. 2010;49:862–75.

    Article  PubMed  CAS  Google Scholar 

  31. Josefsen L, Droce A, Sondergaard TE, Sorensen JL, Bormann J, Schafer W, et al. Autophagy provides nutrients for nonassimilating fungal structures and is necessary for plant colonization but not for infection in the necrotrophic plant pathogen Fusarium graminearum. Autophagy. 2012;8:326–37.

    Article  PubMed  CAS  Google Scholar 

  32. Anglicheau D, Sharma VK, Ding RC, Hummel A, Snopkowski C, Dadhania D, et al. MicroRNA expression profiles predictive of human renal allograft status. Proc Natl Acad Sci USA. 2009;106(13):5330–5.

    Article  PubMed  CAS  Google Scholar 

  33. Kokkonen H, Soderstrom I, Rocklov J, Hallmans G, Lejon K, Dahlqvist SR. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 2010;62(2):383–91.

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Jianbing Ma and Yumin Zhang for the collection of specimens. This study was supported by the National Natural Science Foundation of China (No. 81171742) and Shaanxi Province Science and Technology Projects (No. 2008K-38).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Joint Surgery, Hong Hui Hospital, Xi’an Jiaotong University College of Medicine, Xi’an, 710054, China

    Ke Xu, Peng Xu, Jian-Feng Yao & Wei-kun Hou

  2. Department of Orthopedics, First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, 710061, China

    Yin-Gang Zhang

  3. Department of Genetics and Molecular Biology, Xi’an Jiaotong University College of Medicine, Xi’an, 710061, China

    She-Min Lu

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  1. Ke Xu
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Correspondence to Peng Xu or She-Min Lu.

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Responsible Editor: John Di Battista.

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Xu, K., Xu, P., Yao, JF. et al. Reduced apoptosis correlates with enhanced autophagy in synovial tissues of rheumatoid arthritis. Inflamm. Res. 62, 229–237 (2013). https://doi.org/10.1007/s00011-012-0572-1

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  • DOI: https://doi.org/10.1007/s00011-012-0572-1

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