Skip to main navigation menu Skip to main content Skip to site footer
##common.pageHeaderLogo.altText##

Review article: Biomedical intelligence

Vol. 142 No. 0708 (2012)

Fibroblasts as therapeutic targets in rheumatoid arthritis and cancer

  • Maria Juarez
  • Andrew Filer
  • Christopher D. Buckley
DOI
https://doi.org/10.4414/smw.2012.13529
Cite this as:
Swiss Med Wkly. 2012;142:w13529
Published
12.02.2012

Summary

Rheumatoid arthritis (RA) is a common chronic inflammatory disease that causes progressive synovial inflammation resulting in irreversible joint destruction, chronic disability and premature mortality [1, 2]. Although it is recognised that in RA, inflammation and its persistence result from complex interactions between haematopoietic and stromal cells [3–5], research into the pathogenesis of the disease has traditionally concentrated on cells and cytokines of the immune system, neglecting the role of stromal cells. As a consequence, new biologic treatments have been developed, which have led to a step-change in the management of the disease [6]. Nevertheless, these treatments do not reverse tissue damage or lead to disease cure and are not effective for all patients. Furthermore, at best they induce a significant clinical response (ACR70) in less than 60% of patients, most of whom will relapse on treatment withdrawal, suggesting that additional therapeutic targets, responsible for complete resolution of inflammation, remain to be discovered [7]. An increasing body of evidence implicates RA synovial fibroblasts in driving the persistent, destructive characteristics of the disease. In this paper, we discuss the evidence implicating synovial fibroblasts in the pathogenesis of RA and explore their role as therapeutic targets.

References

  1. Scott DL, Pugner K, Kaarela K, Doyle DV, Woolf A, Holmes J, et al. The links between joint damage and disability in rheumatoid arthritis. Rheumatology. (Oxford) 2000;39:122–32.
  2. Kitas GD, Erb N. Tackling ischaemic heart disease in rheumatoid arthritis. Rheumatology. (Oxford) 2003;42:607–13.
  3. Buckley CD, Pilling D, Lord JM, Akbar AN, Scheel-Toellner D, Salmon M. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol. 2001;22:199–204.
  4. Parsonage G, Filer AD, Haworth O, Nash GB, Rainger GE, Salmon M, et al. A stromal address code defined by fibroblasts. Trends Immunol. 2005;26:150–6.
  5. Burman A, Haworth O, Hardie DL, Amft EN, Siewert C, Jackson DG, et al. A chemokine-dependent stromal induction mechanism for aberrant lymphocyte accumulation and compromised lymphatic return in rheumatoid arthritis. J Immunol. 2005;174:1693–700.
  6. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol. 2007;7:429–42.
  7. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–19.
  8. van der Helm-van Mil AH, Wesoly JZ, Huizinga TW. Understanding the genetic contribution to rheumatoid arthritis. Curr Opin Rheumatol. 2005;17:299–304.
  9. Klareskog L, Padyukov L, Alfredsson L. Smoking as a trigger for inflammatory rheumatic diseases. Curr Opin Rheumatol. 2007;19:49–54.
  10. Firestein GS. Evolving concepts of rheumatoid arthritis. Nature. 2003;423:356–61.
  11. Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon WM, et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol. 2001;167:1072–80.
  12. Taylor PC, Sivakumar B. Hypoxia and angiogenesis in rheumatoid arthritis. Curr Opin Rheumatol. 2005;17:293–8.
  13. Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol. 2003;15:15–21.
  14. Iwamoto T, Okamoto H, Toyama Y, Momohara S. Molecular aspects of rheumatoid arthritis: chemokines in the joints of patients. FEBS J. 2008;275:4448–55.
  15. Buckley CD, Amft N, Bradfield PF, Pilling D, Ross E, Arenzana-Seisdedos F, et al. Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol. 2000;165:3423–9.
  16. Bradfield PF, Amft N, Vernon-Wilson E, Exley AE, Parsonage G, Rainger GE, et al. Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 2003;48:2472–82.
  17. Buckley CD. Michael Mason prize essay 2003. Why do leucocytes accumulate within chronically inflamed joints? Rheumatology. (Oxford) 2003;42:1433–44.
  18. Ohata J, Zvaifler NJ, Nishio M, Boyle DL, Kalled SL, Carson DA, et al. Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol. 2005;174:864–70.
  19. Pilling D, Akbar AN, Girdlestone J, Orteu CH, Borthwick NJ, Amft N, et al. Interferon-beta mediates stromal cell rescue of T cells from apoptosis. Eur J Immunol. 1999;29:1041–50.
  20. Filer A, Parsonage G, Smith E, Osborne C, Thomas AM, Curnow SJ, et al. Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: site-specific versus activation-dependent survival of T cells and neutrophils. Arthritis Rheum. 2006;54:2096–108.
  21. Burger JA, Zvaifler NJ, Tsukada N, Firestein GS, Kipps TJ. Fibroblast-like synoviocytes support B-cell pseudoemperipolesis via a stromal cell-derived factor-1- and CD106 (VCAM-1)-dependent mechanism. J Clin Invest. 2001;107:305–15.
  22. Muller-Ladner U, Gay S. MMPs and rheumatoid synovial fibroblasts: Siamese twins in joint destruction? Ann Rheum Dis. 2002;61:957–9.
  23. Pap T, Muller-Ladner U, Gay RE, Gay S. Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res. 2000;2:361–7.
  24. Takayanagi H, Iizuka H, Juji T, Nakagawa T, Yamamoto A, Miyazaki T, et al. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum. 2000;43:259–69.
  25. Muller-Ladner 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.
  26. Tolboom TC, van der Helm-van Mil AH, Nelissen RG, Breedveld FC, Toes RE, Huizinga TW. Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis Rheum. 2005;52:1999–2002.
  27. Qu Z, Garcia CH, O'Rourke LM, Planck SR, Kohli M, Rosenbaum JT. Local proliferation of fibroblast-like synoviocytes contributes to synovial hyperplasia. Results of proliferating cell nuclear antigen/cyclin, c-myc, and nucleolar organizer region staining. Arthritis Rheum. 1994;37:212–20.
  28. Rinaldi N, Schwarz-Eywill M, Weis D, Leppelmann-Jansen P, Lukoschek M, Keilholz U, et al. Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann Rheum Dis. 1997;56:45–51.
  29. Westhoff CS, Freudiger D, Petrow P, Seyfert C, Zacher J, Kriegsmann J, et al. Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA expression in the synovial membrane and synovial fibroblasts of patients with rheumatoid arthritis. Arthritis Rheum. 1999;42:1517–27.
  30. Pap T, Shigeyama Y, Kuchen S, Fernihough JK, Simmen B, Gay RE, et al. Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum. 2000;43:1226–32.
  31. 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.
  32. Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci. USA 2002;99:12877–82.
  33. Krumlauf R. Hox genes in vertebrate development. Cell. 1994;78:191–201.
  34. Tabin CJ. Why we have (only) five fingers per hand: hox genes and the evolution of paired limbs. Development. 1992;116:289–96.
  35. Bird A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16:6–21.
  36. Rinn JL, Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell. 2007;129:1311–23.
  37. Karouzakis E, Gay RE, Michel BA, Gay S, Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 2009;60:3613-22.
  38. Micke P, Ostman A. Tumour-stroma interaction: cancer-associated fibroblasts as novel targets in anti-cancer therapy? Lung Cancer. 2004;45(Suppl 2):S163–S175.
  39. De WO, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003;200:429–47.
  40. Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB. Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol. 1999;277:C1–C9.
  41. Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001;264:169–84.
  42. Moustakas A, Souchelnytskyi S, Heldin CH. Smad regulation in TGF-beta signal transduction. J Cell Sci. 2001;114:4359–69.
  43. Piek E, Heldin CH, Ten DP. Specificity, diversity, and regulation in TGF-beta superfamily signaling. FASEB J. 1999;13:2105–24.
  44. Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD, Cunha GR. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 1999;59:5002–11.
  45. Kuperwasser C, Chavarria T, Wu M, Magrane G, Gray JW, Carey L, et al. Reconstruction of functionally normal and malignant human breast tissues in mice. Proc Natl Acad Sci U S A. 2004;101:4966–71.
  46. Capdeville R, Buchdunger E, Zimmermann J, Matter A. Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nat Rev Drug Discov. 2002;1:493–502.
  47. Bonafoux D, Lee WC. Strategies for TGF-beta modulation: a review of recent patents. Expert Opin Ther Pat. 2009;19:1759–69.
  48. Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, et al. A Phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9:1639–47.
  49. Cheng JD, Dunbrack RL, Jr., Valianou M, Rogatko A, Alpaugh RK, Weiner LM. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res. 2002;62:4767–72.
  50. Welt S, Divgi CR, Scott AM, Garin-Chesa P, Finn RD, Graham M, et al. Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts. J Clin Oncol. 1994;12:1193–203.
  51. Jiang L, Gonda TA, Gamble MV, Salas M, Seshan V, Tu S, et al. Global hypomethylation of genomic DNA in cancer-associated myofibroblasts. Cancer Res. 2008;68:9900–8.
  52. Raj K, Mufti GJ. Azacytidine (Vidaza(R)) in the treatment of myelodysplastic syndromes. Ther Clin Risk Manag. 2006;2:377–88.
  53. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40.
  54. Wendling D, Prati C, Toussirot E, Herbein G. Targeting intracellular signaling pathways to treat rheumatoid arthritis: Pandora's box? Joint Bone Spine. 2010;77:96–8.
  55. Paniagua RT, Sharpe O, Ho PP, Chan SM, Chang A, Higgins JP, et al. Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006;116:2633–42.
  56. Terabe F, Kitano M, Kawai M, Kuwahara Y, Hirano T, Arimitsu J, et al. Imatinib mesylate inhibited rat adjuvant arthritis and PDGF-dependent growth of synovial fibroblast via interference with the Akt signaling pathway. Mod Rheumatol. 2009;19:522–9.
  57. Valencia X, Higgins JM, Kiener HP, Lee DM, Podrebarac TA, Dascher CC, et al. Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J Exp Med. 2004;200:1673–9.
  58. Lee DM, Kiener HP, Agarwal SK, Noss EH, Watts GF, Chisaka O, et al. Cadherin-11 in synovial lining formation and pathology in arthritis. Science. 2007;315:1006–10.
  59. MacFadyen JR, Haworth O, Roberston D, Hardie D, Webster MT, Morris HR, et al. Endosialin (TEM1, CD248) is a marker of stromal fibroblasts and is not selectively expressed on tumour endothelium. FEBS Lett. 2005;579:2569–75.
  60. Lax S, Hou TZ, Jenkinson E, Salmon M, MacFadyen JR, Isacke CM, et al. CD248/Endosialin is dynamically expressed on a subset of stromal cells during lymphoid tissue development, splenic remodeling and repair. FEBS Lett. 2007;581:3550–6.
  61. Tomkowicz B, Rybinski K, Sebeck D, Sass P, Nicolaides NC, Grasso L, et al. Endosialin/TEM-1/CD248 regulates pericyte proliferation through PDGF receptor signaling. Cancer Biol Ther. 2010;9:908–15.
  62. Maia M, de VA, Janssens T, Moons M, van LK, Tavernier J, et al. CD248 and its cytoplasmic domain: a therapeutic target for arthritis. Arthritis Rheum. 2010;62:3595–606.
  63. Brentano F, Schorr O, Ospelt C, Stanczyk J, Gay RE, Gay S, et al. Pre-B cell colony-enhancing factor/visfatin, a new marker of inflammation in rheumatoid arthritis with proinflammatory and matrix-degrading activities. Arthritis Rheum. 2007;56:2829–39.
  64. Evans L, Williams AS, Hayes AJ, Jones SA, Nowell M. Suppression of leukocyte infiltration and cartilage degradation by selective inhibition of pre-B cell colony-enhancing factor/visfatin/nicotinamide phosphoribosyltransferase: Apo866-mediated therapy in human fibroblasts and murine collagen-induced arthritis. Arthritis Rheum. 2011;63:1866–77.
  65. Ospelt C, Mertens JC, Jungel A, Brentano F, Maciejewska-Rodriguez H, Huber LC, et al. Inhibition of fibroblast activation protein and dipeptidylpeptidase 4 increases cartilage invasion by rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2010;62:1224–35.
  66. Jungel A, Baresova V, Ospelt C, Simmen BR, Michel BA, Gay RE, et al. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann Rheum Dis. 2006;65:910–2.
  67. Nasu Y, Nishida K, Miyazawa S, Komiyama T, Kadota Y, Abe N, et al. Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis Cartilage. 2008;16:723–32.
  68. Stefani G, Slack FJ. Small non-coding RNAs in animal development. Nat Rev Mol Cell Biol. 2008;9:219–30.
  69. Stanczyk J, Ospelt C, Karouzakis E, Filer A, Raza K, Kolling C, et al. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum. 2011;63:373–81.
  70. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol. 2010;28:1057–68.
  71. Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, et al. Selective inhibition of BET bromodomains. Nature. 2010;468:1067–73.