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Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis

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Abstract

We undertook this study to determine whether the altered expression of telomeric proteins TPP1 and POT1 in fibroblast-like synovial cells (FLS) could provide insights into the pathogenesis of rheumatoid arthritis (RA). FLS were isolated from patients with RA, osteoarthritis (OA) and traumatic joint disease, and cultured in vitro. TPP1 and POT1 mRNA level of FLS were measured using real-time quantitative polymerase chain reaction (RT-qPCR) in 42 RA, 23 OA and 13 healthy cases. Immunofluorescence staining and Western blot were used to detect the expression of TPP1 and POT1 protein. Expression of TPP1 and POT1 mRNA was significantly reduced in RA cases (P < 0.001, respectively), and no significant difference was observed between OA and healthy cases (P > 0.05, respectively). Confocal microscopy images showed TPP1 and POT1 proteins mainly located in nucleus of FLS. Western blot demonstrated that TPP1 protein level was significantly reduced in RA cases (P < 0.001), and POT1 protein expression was not statistical significance among RA, OA patients and healthy cases (P > 0.05). Significant negative correlation was observed between level of TPP1 mRNA and titers of anti-CCP antibody (P < 0.001), RF (P < 0.01). Altered expression of TPP1 might contribute to persistent proliferation of FLS in RA, further study on functions of telomeric proteins in RA would be needed.

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References

  1. Huber LC, Distler O, Tarner I et al (2006) Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford) 45:669–675

    Article  CAS  Google Scholar 

  2. Shore D (2001) Telomeric chromatin: replicating and wrapping up chromosome ends. Curr Opin Genet Dev 11:189–198

    Article  PubMed  CAS  Google Scholar 

  3. Cohen SB, Graham ME, Lovrecz GO et al (2007) Protein composition of catalytically active human telomerase from immortal cells. Science 315:1850–1853

    Article  PubMed  CAS  Google Scholar 

  4. de Lange T (2005) Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 19:2100–2110

    Article  PubMed  Google Scholar 

  5. Gilson E, Geli V (2007) How telomeres are replicated. Nat Rev Mol Cell Biol 8:825–838

    Article  PubMed  CAS  Google Scholar 

  6. Wang F, Podell ER, Zaug AJ et al (2007) The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature 445:506–510

    Article  PubMed  CAS  Google Scholar 

  7. Xin H, Liu D, Wan M et al (2007) TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature 445:559–562

    Article  PubMed  CAS  Google Scholar 

  8. Houghtaling BR, Cuttonaro L, Chang W et al (2004) A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol 14:1621–1631

    Article  PubMed  CAS  Google Scholar 

  9. Kim S, Beausejour C, Davalos AR et al (2004) TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem 279:43799–43804

    Article  PubMed  CAS  Google Scholar 

  10. Liu D, Safari A, O’Connor MS et al (2004) PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol 6:673–680

    Article  PubMed  CAS  Google Scholar 

  11. Liu D, O’Connor MS, Qin J et al (2004) Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem 279:51338–51342

    Article  PubMed  CAS  Google Scholar 

  12. Ye JZ, Hockemeyer D, Krutchinsky AN et al (2004) POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev 18:1649–1654

    Article  PubMed  CAS  Google Scholar 

  13. Ye JZ, Donigian JR, van Overbeek M et al (2004) TIN2 binds TRF1 and TRF2 simultaneously and stabilizes the TRF2 complex on telomeres. J Biol Chem 279:47264–47271

    Article  PubMed  CAS  Google Scholar 

  14. Yang Q, Zheng YL, Harris CC (2005) POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 25:1070–1080

    Article  PubMed  CAS  Google Scholar 

  15. O’Connor MS, Safari A, Xin H et al (2006) A critical role for TPP1 and TIN2 interaction in high-order telomeric complex assembly. Proc Natl Acad Sci USA 103:11874–11879

    Article  PubMed  Google Scholar 

  16. Verdun RE, Crabbe L, Haggblom C et al (2005) Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 20:551–561

    Article  PubMed  CAS  Google Scholar 

  17. Verdun RE, Karlseder J (2007) Replication and protection of telomeres. Nature 447:924–931

    Article  PubMed  CAS  Google Scholar 

  18. Yamanishi Y, Hiyama K, Maeda H et al (1998) Telomerase activity in rheumatoid synovium correlates with the mononuclear cell infiltration level and disease aggressiveness of rheumatoid arthritis. J Rheumatol 25:214–220

    PubMed  CAS  Google Scholar 

  19. Yudoh K, Matsuno H, Nezuka T et al (1999) Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis: the role of telomerase activity in synovial proliferation. Arthritis Rheum 42:669–677

    Article  PubMed  CAS  Google Scholar 

  20. Tsumuki H, Hasunuma T, Kobata T et al (2000) Basic FGF-induced activation of telomerase in rheumatoid synoviocytes. Rheumatol Int 19:123–128

    Article  PubMed  CAS  Google Scholar 

  21. Steer SE, Williams FM, Kato B et al (2007) Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration. Ann Rheum Dis 66:476–480

    Article  PubMed  CAS  Google Scholar 

  22. Tarhan F, Vural F, Kosova B et al (2008) Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol Int 28:579–583

    Article  PubMed  CAS  Google Scholar 

  23. Kondo T, Oue N, Yoshida K et al (2004) Expression of POT1 is associated with tumor stage and telomere length in gastric carcinoma. Cancer Res 64:523–529

    Article  PubMed  CAS  Google Scholar 

  24. Muller-Ladner U, Kriegsmann J, Franklin BN et al (1996) Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 149:1607–1615

    PubMed  CAS  Google Scholar 

  25. Stanczyk J, Ospelt C, Gay RE et al (2006) Synovial cell activation. Curr Opin Rheumatol 18:262–267

    Article  PubMed  CAS  Google Scholar 

  26. Arnett FC, Edworthy SM, Bloch DA et al (1998) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    Article  Google Scholar 

  27. Altman R, Asch E, Bloch D et al (1986) Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and therapeutic criteria committee of the American Rheumatism Association. Arthritis Rheum 29:1039–1049

    Article  PubMed  CAS  Google Scholar 

  28. Scanu A, Oliviero F, Braghetto L et al (2007) Synoviocyte cultures from synovial fluid. Reumatism 59:66–70

    CAS  Google Scholar 

  29. Yamanishi Y, Boyle DL, Green DR et al (2005) P53 tumor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis. Arthritis Res Ther 7:R12–R18

    Article  PubMed  CAS  Google Scholar 

  30. Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47

    Article  PubMed  Google Scholar 

  31. Gil ME, Coetzer TL (2004) Real-time quantitative PCR of telomere length. Mol Biotechnol 27:169–172

    Article  PubMed  CAS  Google Scholar 

  32. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C (T) method. Nat Protoc 3:1101–1108

    Article  PubMed  CAS  Google Scholar 

  33. Stebulis JA, Rossetti RG, Atez FJ et al (2005) Fibroblast-like synovial cells derived from synovial fluid. J Rheumatol 32:301–306

    PubMed  CAS  Google Scholar 

  34. Zvaifler NJ (1995) Rheumatoid arthritis. The multiple pathways to chronic synovitis. Lab Invest 73:307–310

    PubMed  CAS  Google Scholar 

  35. Panayi GS (1997) T-cell-dependent pathways in rheumatoid arthritis. Curr Opin Rheumatol 9:236–240

    Article  PubMed  CAS  Google Scholar 

  36. Fox DA (1997) The role of T cells in the immunopathogenesis of rheumatoid arthritis: new perspectives. Arthritis Rheum 40:598–609

    Article  PubMed  CAS  Google Scholar 

  37. KoopmanWJ GayS (1993) Do nonimmunologically mediated pathways play a role in the pathogenesis of rheumatoid arthritis? Rheum Dis Clin North Am 19:107–122

    Google Scholar 

  38. Imamura F, Aono H, Hasunuma T et al (1998) Monoclonal expansion of synoviocytes in rheumatoid arthritis. Arthritis Rheum 41:1979–1986

    Article  PubMed  CAS  Google Scholar 

  39. Aupperle KR, Boyle DL, Hendrix M et al (1998) Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene. Am J Pathol 52:1091–1098

    Google Scholar 

  40. Reme T, Travaglio A, Gueydon E et al (1998) Mutation of the p53 tumour suppressor gene in erosive rheumatoid synovial tissue. Clin Exp Immunol 111:353–358

    Article  PubMed  CAS  Google Scholar 

  41. Dooley S, Herlitzka I, Hanselmann R et al (1996) Constitutive expression of c-fos and c-jun, overexpression of ets-2, and reduced expression of metastasis suppressor gene nm23-H1 in rheumatoid arthritis. Ann Rheum Dis 55:298–304

    Article  PubMed  CAS  Google Scholar 

  42. Kontny E, Ziolkowska M, Dudzinka E et al (1995) Modified expression of c-Fos and c-Jun proteins and production of interleukin-1 beta in patients with rheumatoid arthritis. Clin Exp Rheumatol 13:51–57

    PubMed  CAS  Google Scholar 

  43. Pap T, Nawrath M, Heinrich J et al (2004) Cooperation of Ras and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum 50:2794–2802

    Article  PubMed  CAS  Google Scholar 

  44. Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015

    Article  PubMed  CAS  Google Scholar 

  45. Kelleher C, Kurth I, Lingner J (2005) Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol 25:808–818

    Article  PubMed  CAS  Google Scholar 

  46. Bunch JT, Bae NS, Leonardi J et al (2005) Distinct requirements for Pot1 in limiting telomere length and maintaining chromosome stability. Mol Cell Biol 25:5567–5678

    Article  PubMed  CAS  Google Scholar 

  47. Miyoshi T, Kanoh J, Saito M et al (2008) Fission yeast Pot1-Tpp1 protects telomeres and regulates telomere length. Science 320:1341–1344

    Article  PubMed  CAS  Google Scholar 

  48. Guo X, Deng Y, Lin Y et al (2007) Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J 26:4709–4719

    Article  PubMed  CAS  Google Scholar 

  49. Nishimura K, Sugiyama D, Kogata Y et al (2007) Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 146:797–808

    PubMed  Google Scholar 

  50. Chen LY, Liu D, Songyang Z (2007) Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol 27:5898–5909

    Article  PubMed  CAS  Google Scholar 

  51. Mackay JMK, Panayi G, Neill WA et al (1974) Cytology of rheumatoid synovial cells in culture. I. Composition and sequence of cell populations in cultures of rheumatoid synovial fluid. Ann Rheum Dis 33:225–233

    Article  PubMed  CAS  Google Scholar 

  52. Panayi GS, Mackay JM, Neill WA et al (1974) Cytology of rheumatoid synovial cells in culture. II. Association of polykaryocytes with rheumatoid and other forms of arthritis. Ann Rheum Dis 33:234–239

    Article  PubMed  CAS  Google Scholar 

  53. Neidhart M, Seemayer CA, Hummel KM et al (2003) Functional characterization of adherent synovial fluid cells in rheumatoid arthritis: destructive potential in vitro and in vivo. Arthritis Rheum 48:1873–1880

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the Department of Health of Sichuan, PR China (grant number: 080099).

Conflict of interest

All the authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Institute of Rheumatology and Immunology and Department of Rheumatology and Hematology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China

    Yu-Feng Qing, Jing-Guo Zhou & Qi-Bin Yang

  2. Institute of Rheumatology and Immunology and Department of Clinical Laboratory, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China

    Ming-Cai Zhao & Yan Xing

  3. Institute of Rheumatology and Immunology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, China

    Wen-Guang Xie & Hong Jiang

  4. Department of Rheumatology, The Affiliated Hospital of Chengdu University of TCM, Chengdu, Sichuan, China

    Sheng-Ping Zeng

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  1. Yu-Feng Qing
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Correspondence to Jing-Guo Zhou.

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Qing, YF., Zhou, JG., Zhao, MC. et al. Altered expression of TPP1 in fibroblast-like synovial cells might be involved in the pathogenesis of rheumatoid arthritis. Rheumatol Int 32, 2503–2510 (2012). https://doi.org/10.1007/s00296-011-1992-x

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