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Epigenetic control in rheumatoid arthritis synovial fibroblasts

Abstract

Rheumatoid arthritis synovial fibroblasts (RASFs) are the effector cells of cartilage and bone destruction. These cells show an 'intrinsically' activated and aggressive phenotype that results in the increased production of matrix-degrading enzymes and adhesion molecules, and is conserved over long-term passage in vitro. The three main mechanisms of epigenetic control—DNA methylation, histone modifications and microRNA activity—interact in the development of the RASF phenotype. The extent of global DNA methylation is reduced in synoviocytes in situ and RASFs in vitro. In addition, histone hyperacetylation occurs and specific microRNAs are expressed in RASFs. Normal synovial fibroblasts cultured in a hypomethylating milieu acquire an activated phenotype similar to that of RASFs. These findings suggest that epigenetic control, in particular the control of DNA methylation, is deficient in RASFs. Genome-wide analyses of the epigenome will enable the detection of additional genes involved in the pathogenesis of rheumatoid arthritis, the identification of epigenetic biomarkers, and potentially the development of a therapeutic regimen that targets activated RASFs.

Key Points

  • Rheumatoid arthritis synovial fibroblasts (RASFs) exhibit an aggressive phenotype that is characterized by the expression of matrix-degrading enzymes and adhesion molecules

  • The aggressive RASF phenotype can be induced in normal synovial fibroblasts by culture in a hypomethylating milieu

  • Histone modifications and microRNA binding have also been implicated in the development of RASF phenotype, which suggests that all three epigenetic pathways are altered in rheumatoid arthritis

  • Whole-epigenome analysis could lead to the discovery of novel genes and epigenetic biomarkers involved in the pathogenesis of rheumatoid arthritis, with potential implications for treatment

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Figure 1: Epigenetic regulation of gene expression integrates both genetic and environmental factors.
Figure 2: Differentiation of mesenchymal stem cells into fibroblasts is under epigenetic control, mainly via methylation or demethylation of specific promoter regions, which either enables or disables the expression of the relevant gene.
Figure 3: The aggressive phenotype of rheumatoid arthritis synovial fibroblasts can be, in great part, reproduced by treating normal fibroblasts with a DNA methyltransferase inhibitor, such as azacytidine, which induces global DNA hypomethylation.
Figure 4: Methods used to analyze DNA methylation.

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References

  1. Eggermann, T., Meyer, E., Caglayan, A. O., Dundar, M. & Schonherr, N. ICR1 epimutations in llp15 are restricted to patients with Silver–Russell syndrome features. J. Pediatr. Endocrinol. Metab. 21, 59–62 (2008).

    Article  Google Scholar 

  2. Hauke, J. et al. Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition. Hum. Mol. Genet. 18, 304–317 (2009).

    Article  CAS  Google Scholar 

  3. Gerli, R. et al. Precocious atherosclerosis in rheumatoid arthritis: role of traditional and disease-related cardiovascular risk factors. Ann. NY Acad. Sci. 1108, 372–381 (2007).

    Article  CAS  Google Scholar 

  4. Stöger, R. Epigenetics and obesity. Pharmacogenomics 9, 1851–1860 (2008).

    Article  Google Scholar 

  5. Chiang, P. K., Lam, M. A. & Luo, Y. The many faces of amyloid β in Alzheimer's disease. Curr. Mol. Med. 8, 580–584 (2008).

    Article  CAS  Google Scholar 

  6. Sokka, T. et al. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study. Arthritis Res. Ther. 11, R7 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. Lu, Q. et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J. Immunol. 179, 6352–6358 (2007).

    Article  CAS  Google Scholar 

  8. Javierre, B. M., Esteller, M. & Ballestar, E. Epigenetic connections between autoimmune disorders and haematological malignancies. Trends Immunol. 29, 616–623 (2008).

    Article  CAS  Google Scholar 

  9. Singal, R. & Ginder, G. D. DNA methylation. Blood 93, 4059–4070 (1999).

    CAS  PubMed  Google Scholar 

  10. Bird, A. DNA methylation patterns and epigenetic memory. Genes Dev. 16, 6–21 (2002).

    Article  CAS  Google Scholar 

  11. Turek-Plewa, J. & Jagodzinski, P. P. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol. Biol. Lett. 10, 631–647 (2005).

    CAS  PubMed  Google Scholar 

  12. Issa, J. P. CpG island methylator phenotype in cancer. Nat. Rev. Cancer 4, 988–993 (2004).

    Article  CAS  Google Scholar 

  13. Ballestar, E. & Esteller, M. Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger. Biochem. Cell Biol. 83, 374–384 (2005).

    Article  CAS  Google Scholar 

  14. Robertson, K. D. DNA methylation and human disease. Nat. Rev. Genet. 6, 597–610 (2005).

    Article  CAS  Google Scholar 

  15. Pountos, I., Corscadden, D., Emery, P. & Giannoudis, P. V. Mesenchymal stem cell tissue engineering: techniques for isolation, expansion and application. Injury 38 (Suppl. 4), S23–S33 (2007).

    Article  Google Scholar 

  16. Boquest, A. C., Noer, A. & Collas, P. Epigenetic programming of mesenchymal stem cells from human adipose tissue. Stem Cell Rev. 2, 319–329 (2006).

    Article  CAS  Google Scholar 

  17. Takada, I., Suzawa, M., Matsumoto, K. & Kato, S. Suppression of PPAR transactivation switches cell fate of bone marrow stem cells from adipocytes into osteoblasts. Ann. NY Acad. Sci. 1116, 182–195 (2007).

    Article  CAS  Google Scholar 

  18. Nolte, S. V., Xu, W., Rennekampff, H. O. & Rodemann, H. P. Diversity of fibroblasts—a review on implications for skin tissue engineering. Cells Tissues Organs 187, 165–176 (2008).

    Article  Google Scholar 

  19. Karouzakis, E., Neidhart, M., Gay, R. E. & Gay, S. Molecular and cellular basis of rheumatoid joint destruction. Immunol. Lett. 106, 8–13 (2006).

    Article  CAS  Google Scholar 

  20. Bauer, S. et al. Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res. Ther. 8, R171 (2006).

    Article  Google Scholar 

  21. Muller-Ladner, U., Pap, T., Gay, R. E., Neidhart, M. & Gay, S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat. Clin. Pract. Rheumatol. 1, 102–110 (2005).

    Article  Google Scholar 

  22. Lafyatis, R. et al. Anchorage-independent growth of synoviocytes from arthritic and normal joints. Stimulation by exogenous platelet-derived growth factor and inhibition by transforming growth factor-β and retinoids. J. Clin. Invest. 83, 1267–1276 (1989).

    Article  CAS  Google Scholar 

  23. Konttinen, Y. T. et al. Analysis of 16 different matrix metalloproteinases (MMP-1 to MMP-20) in the synovial membrane: different profiles in trauma and rheumatoid arthritis. Ann. Rheum. Dis. 58, 691–697 (1999).

    Article  CAS  Google Scholar 

  24. Rinaldi, N. et al. Differential expression and functional behaviour of the αv and β3 integrin subunits in cytokine-stimulated fibroblast-like cells derived from synovial tissue of rheumatoid arthritis and osteoarthritis in vitro. Ann. Rheum. Dis. 56, 729–736 (1997).

    Article  CAS  Google Scholar 

  25. Firestein, G. S., Alvaro-Gracia, J. M. & Maki, R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol. 144, 3347–3353 (1990).

    CAS  PubMed  Google Scholar 

  26. Huber, L. C. et al. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum. 56, 1087–1093 (2007).

    Article  CAS  Google Scholar 

  27. Stanczyk, J. et al. Altered expression of µRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 58, 1001–1009 (2008).

    Article  Google Scholar 

  28. Neidhart, M. et al. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum. 43, 2634–2647 (2000).

    Article  CAS  Google Scholar 

  29. Ali, M. et al. Overexpression of transcripts containing LINE-1 in the synovia of patients with rheumatoid arthritis. Ann. Rheum. Dis. 62, 663–666 (2003).

    Article  CAS  Google Scholar 

  30. Kuchen, S. et al. The L1 retroelement-related p40 protein induces p38δ MAP kinase. Autoimmunity 37, 57–65 (2004).

    Article  CAS  Google Scholar 

  31. Karouzakis, E. et al. Genomic hypomethylation of rheumatoid arthritis synovial fibroblasts [abstract 745]. Arthritis Rheum. 56 (Suppl.), S317 (2007).

    Google Scholar 

  32. Schulz, W. A., Steinhoff, C. & Florl, A. R. Methylation of endogenous human retroelements in health and disease. Curr. Top. Microbiol. Immunol. 310, 211–250 (2006).

    CAS  PubMed  Google Scholar 

  33. Nile, C. J., Read, R. C., Akil, M., Duff, G. W. & Wilson, A. G. Methylation status of a single CpG site in the IL6 promoter is related to IL-6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 58, 2686–2693 (2008).

    Article  Google Scholar 

  34. Kimura, F. et al. Decrease of DNA methyltransferase 1 expression relative to cell proliferation in transitional cell carcinoma. Int. J. Cancer 104, 568–578 (2003).

    Article  CAS  Google Scholar 

  35. Karouzakis, E., Gay, R. E., Kolling, C., Gay, S. & Neidhart, M. Epigenetic profile of gene expression in normal and rheumatoid arthritis synovial fibroblasts [abstract 939]. Arthritis Rheum. 58 (Suppl.), S514 (2008).

    Google Scholar 

  36. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    Article  CAS  Google Scholar 

  37. Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S. & Neidhart, M. The increased expression of β1 integrin (CD29) in rheumatoid synovial fibroblasts is due to a milieu favouring genomic hypomethylation [abstract OP-0110]. Ann. Rheum. Dis. 67 (Suppl. II), 84 (2008).

    Google Scholar 

  38. Hmadcha, A., Bedoya, F. J., Sobrino, F. & Pintado, E. Methylation-dependent gene silencing induced by interleukin 1β via nitric oxide production. J. Exp. Med. 190, 1595–1604 (1999).

    Article  CAS  Google Scholar 

  39. Wehbe, H., Henson, R., Meng, F., Mize-Berge, J. & Patel, T. Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res. 66, 10517–10524 (2006).

    Article  CAS  Google Scholar 

  40. Hodge, D. R. et al. IL-6 enhances the nuclear translocation of DNA cytosine-5-methyltransferase 1 (DNMT1) via phosphorylation of the nuclear localization sequence by Akt kinase. Cancer Genomics Proteomics 4, 387–398 (2007).

    CAS  PubMed  Google Scholar 

  41. Chuang, L. S. et al. Human DNA-(cytosine-5)-methyltransferase–PCNA complex as a target for p21waf1. Science 277, 1996–2000 (1997).

    Article  CAS  Google Scholar 

  42. Szyf, M. The role of DNA methyltransferase 1 in growth control. Front. Biosci. 6, D599–D609 (2001).

    Article  CAS  Google Scholar 

  43. Deng, J. & Szyf, M. Downregulation of DNA (cytosine-5)-methyltransferase is a late event in NGF-induced PC12 cell differentiation. Brain Res. Mol. Brain Res. 71, 23–31 (1999).

    Article  CAS  Google Scholar 

  44. Esteller, M. Epigenetics in cancer. N. Engl. J. Med. 358, 1148–1159 (2008).

    Article  CAS  Google Scholar 

  45. Takami, N. et al. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum. 54, 779–787 (2006).

    Article  CAS  Google Scholar 

  46. Karouzakis, E., Gay, R. E., Kolling, C., Gay, S. & Neidhart, M. Epigenetic approaches to the study of the pathogenesis of rheumatic disease. Eur. Musculoskeletal Rev. 3, 41–43 (2008).

    Google Scholar 

  47. Clark, S. J., Statham, A., Stirzaker, C., Molloy, P. L. & Frommer, M. DNA methylation: bisulphite modification and analysis. Nat. Protoc. 1, 2353–2364 (2006).

    Article  CAS  Google Scholar 

  48. Tost, J. & Gut, I. G. DNA methylation analysis by pyrosequencing. Nat. Protoc. 2, 2265–2275 (2007).

    Article  CAS  Google Scholar 

  49. Holemon, H. et al. MethylScreen: DNA methylation density monitoring using quantitative PCR. Biotechniques 43, 683–693 (2007).

    Article  CAS  Google Scholar 

  50. Weber, M. et al. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 39, 457–466 (2007).

    Article  CAS  Google Scholar 

  51. Mulero-Navarro, S. & Esteller, M. Epigenetic biomarkers for human cancer: the time is now. Crit. Rev. Oncol. Hematol. 68, 1–11 (2008).

    Article  Google Scholar 

  52. Butcher, L. M. & Beck, S. Future impact of integrated high-throughput methylome analyses on human health and disease. J. Genet. Genomics 35, 391–401 (2008).

    Article  CAS  Google Scholar 

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Correspondence to Michel Neidhart.

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Karouzakis, E., Gay, R., Gay, S. et al. Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nat Rev Rheumatol 5, 266–272 (2009). https://doi.org/10.1038/nrrheum.2009.55

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