Skip to main content

Advertisement

SpringerLink
Log in

Intrazelluläre Signalwege synovialer Fibroblasten bei rheumatoider Arthritis

Intracellular signaling pathways of synovial fibroblasts in rheumatoid arthritis

  • Leitthema
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Noch immer ist die Ätiologie der rheumatoiden Arthritis unbekannt. Die chronische Autoimmunerkrankung manifestiert sich in charakteristischen Gelenkdestruktionen. Untersuchungen der vergangenen Jahre belegen, dass synovialen Fibroblasten eine zentrale Rolle bei Auslösung und Voranschreiten dieser Gelenkveränderungen zukommt. Die Stimulierung der synovialen Fibroblasten über komplexe, miteinander vernetzte intrazelluläre Signalwege führt zu einer stabilen Zellaktivierung, welche auch ohne kontinuierliche Stimulierung durch Entzündungszellen und ihre Mediatoren aufrechterhalten wird. Die pathologische Anheftung an den Gelenkknorpel, die gesteigerte Sekretion matrixzerstörender Enzyme sowie die Veränderungen der Apoptose, dem programmierten Zelltod, stellen die Hauptmerkmale synovialer Fibroblasten von Patienten mit rheumatoider Arthritis dar und resultieren in der progressiven Zerstörung artikulärer Strukturen. Dieser Artikel fasst aktuelle Erkenntnisse zur Aktivierung intrazellulärer Signalwege in Fibroblasten zusammen und zeigt damit mögliche Angriffspunkte für neue Therapieansätze.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease of still unknown etiology that results in characteristic destructive changes of the joints. Research of the past years has demonstrated that synovial fibroblasts play a central role in the initiation and perpetuation of these destructive changes. Stimulation of the synovial fibroblasts through complex and interacting intracellular signaling pathways results in a stable activation that is maintain even without continuous stimulation by inflammatory cells and their mediators. The pathological attachment to articular cartilage, increased secretion of matrix degrading enzymes and alterations in programmed cell death are main characteristics of synovial fibroblasts from patients with RA and result in the progressive destruction of articular structures. The permanent activation of a number of intracellular signaling pathways constitutes the underlying responsible mechanism for the activation of synovial fibroblasts in RA. These signaling pathways do not only show a high degree of complexity, but are also interconnected in multiple ways. This article summarizes recent findings on the activation of intracellular signaling pathways in fibroblasts and points to potential targets for novel therapeutic strategies.

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

Literatur

  1. Buckley CD, Pilling D, Lord JM et al. (2001) Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol 22: 199–204

    Article  PubMed  CAS  Google Scholar 

  2. Müller-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  Google Scholar 

  3. Pap T, Muller-Ladner U, Gay RE, Gay S (2000) Fibroblast biology. Role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2: 361–367

    Article  PubMed  CAS  Google Scholar 

  4. Keffer J, Probert L, Cazlaris H et al. (1991) Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. Embo J 10: 4025–4031

    PubMed  CAS  Google Scholar 

  5. Taylor GA, Carballo E, Lee DM et al. (1996) A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4: 445–454

    Article  PubMed  CAS  Google Scholar 

  6. Dayer JM, Beutler B, Cerami A (1985) Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 162: 2163–2168

    Article  PubMed  CAS  Google Scholar 

  7. Brinckerhoff CE, Auble DT (1990) Regulation of collagenase gene expression in synovial fibroblasts. Ann NY Acad Sci 580: 355–374

    Article  PubMed  CAS  Google Scholar 

  8. van den Berg WB, van de Loo FA, Otterness I et al. (1991) In vivo evidence for a key role of IL-1 in cartilage destruction in experimental arthritis. Agents Actions Suppl 32: 159–163

    Google Scholar 

  9. Shouda T, Yoshida T, Hanada T et al. (2001) Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest 108: 1781–1788

    Article  PubMed  CAS  Google Scholar 

  10. Kurowska M, Rudnicka W, Kontny E et al. (2002) Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bcl-x(L) and Bcl- 2. J Immunol 169: 1760–1767

    PubMed  CAS  Google Scholar 

  11. Bessis N, Boissier MC (2001) Novel pro-inflammatory interleukins: potential therapeutic targets in rheumatoid arthritis. Joint Bone Spine 68: 477–481

    Article  PubMed  CAS  Google Scholar 

  12. Lubberts E, Koenders MI, Berg WB van den (2005) The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 7: 29–37

    Article  PubMed  CAS  Google Scholar 

  13. Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298: 1911–1912

    Article  PubMed  CAS  Google Scholar 

  14. Korb A, Tohidast-Akrad M, Cetin E et al. (2006) Differential expression and activation of p38 MAPK alpha, beta, gamma and delta isoforms in rheumatoid arthritis. Arthritis Rheum 54: 2745–2756

    Article  PubMed  CAS  Google Scholar 

  15. Gortz B, Hayer S, Tuerck B et al. (2005) Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo. Arthritis Res Ther 7: R1140–R1147

    Article  PubMed  CAS  Google Scholar 

  16. Han Z, Boyle DL, Chang L et al. (2001) c-Jun N-terminal kinase is required for metalloproteinase expression and joint destruction in inflammatory arthritis. J Clin Invest 108: 73–81

    Article  PubMed  CAS  Google Scholar 

  17. Koller M, Hayer S, Redlich K et al. (2005) JNK1 is not essential for TNF-mediated joint disease. Arthritis Res Ther 7: R166–R173

    Article  PubMed  CAS  Google Scholar 

  18. Krause A, Scaletta N, Ji JD, Ivashkiv LB (2002) Rheumatoid arthritis synoviocyte survival is dependent on stat3. J Immunol 169: 6610–6616

    PubMed  CAS  Google Scholar 

  19. el Gabalawy H, Wilkins J (1993) Beta 1 (CD29) integrin expression in rheumatoid synovial membranes: an immunohistologic study of distribution patterns. J Rheumatol 20: 231–237

    Google Scholar 

  20. Müller-Ladner U, Elices MJ, Kriegsmann J et al. (1997) Alternatively spliced CS-1 fibronectin isoform and its receptor VLA-4 in rheumatoid synovium demonstrated by in situ hybridization and immunohistochemistry. J Rheumatol 24: 1873–1880

    PubMed  Google Scholar 

  21. Pirila L, Aho H, Roivainen A et al. (2001) Identification of alpha6beta1 integrin positive cells in synovial lining layer as type B synoviocytes. J Rheumatol 28: 478–484

    PubMed  CAS  Google Scholar 

  22. Rinaldi N, Schwarz EM, Weis D et al. (1997) Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins. Ann Rheum Dis 56: 45–51

    Article  PubMed  CAS  Google Scholar 

  23. Sarkissian M, Lafyatis R (1999) Integrin engagement regulates proliferation and collagenase expression of rheumatoid synovial fibroblasts. J Immunol 162: 1772–1779

    PubMed  CAS  Google Scholar 

  24. Ravanti L, Heino J, Lopez-Otin C, Kahari VM (1999) Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem 274: 2446–2455

    Article  PubMed  CAS  Google Scholar 

  25. Wang AZ, Wang JC, Fisher GW, Diamond HS (1997) Interleukin-1beta-stimulated invasion of articular cartilage by rheumatoid synovial fibroblasts is inhibited by antibodies to specific integrin receptors and by collagenase inhibitors. Arthritis Rheum 40: 1298–1307

    PubMed  CAS  Google Scholar 

  26. 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 

  27. Vojtek AB, Der CJ (1998) Increasing complexity of the Ras signaling pathway. J Biol Chem 273: 19.925–19.928

    Article  Google Scholar 

  28. Yamamoto A, Fukuda A, Seto H et al. (2003) Suppression of arthritic bone destruction by adenovirus-mediated dominant-negative Ras gene transfer to synoviocytes and osteoclasts. Arthritis Rheum 48: 2682–2692

    Article  PubMed  CAS  Google Scholar 

  29. Baier A, Meinecke I, Gay S, Pap T (2003) Apoptosis in rheumatoid arthritis. Curr Opin Rheumatol 15: 274–279

    Article  PubMed  CAS  Google Scholar 

  30. Zhang HG, Wang Y, Xie JF et al. (2001) Regulation of tumor necrosis factor alpha-mediated apoptosis of rheumatoid arthritis synovial fibroblasts by the protein kinase Akt. Arthritis Rheum 44: 1555–1567

    Article  PubMed  CAS  Google Scholar 

  31. Drynda A, Quax PH, Neumann M et al. (2005) 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 174: 6524–6531

    PubMed  CAS  Google Scholar 

  32. Hasunuma T, Kayagaki N, Asahara H et al. (1997) Accumulation of soluble Fas in inflamed joints of patients with rheumatoid arthritis. Arthritis Rheum 40: 80–86

    Article  PubMed  CAS  Google Scholar 

  33. Catrina AI, Ulfgren AK, Lindblad S et al. (2002) Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann Rheum Dis 61: 934–936

    Article  PubMed  CAS  Google Scholar 

  34. Schedel J, Gay RE, Kuenzler P et al. (2002) FLICE-inhibitory protein expression in synovial fibroblasts and at sites of cartilage and bone erosion in rheumatoid arthritis. Arthritis Rheum 46: 1512–1518

    Article  PubMed  CAS  Google Scholar 

  35. Perlman H, Georganas C, Pagliari LJ et al. (2000) Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J Immunol 164: 5227–5235

    PubMed  CAS  Google Scholar 

  36. Liu H, Eksarto P, Temkin V et al. (2005). Mcl-1 is esential for the survival of synovial fibroblasts in rheumatoid arthritis. J Immunol 175: 8337–8345

    PubMed  CAS  Google Scholar 

  37. Franz JK, Pap T, Hummel KM et al. (2000) Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43: 599–607

    Article  PubMed  CAS  Google Scholar 

  38. Meinecke I, Cinski A, Baier A et al. (2007) Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts. Proc Natl Acad Sci U S A 104: 5073–5078

    Article  PubMed  CAS  Google Scholar 

Download references

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

Author information

Authors and Affiliations

  1. Bereich molekulare Medizin des Muskuloskelettalen Systems, Universitätsklinikum Münster, Domagkstraße 3, 48129, Münster, Deutschland

    A. Korb, M. Peters, I. Meinecke &  T. Pap

Authors
  1. A. Korb
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Peters
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. Meinecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T. Pap
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T. Pap.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Korb, A., Peters, M., Meinecke, I. et al. Intrazelluläre Signalwege synovialer Fibroblasten bei rheumatoider Arthritis. Z. Rheumatol. 66, 311–316 (2007). https://doi.org/10.1007/s00393-007-0181-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-007-0181-5

Schlüsselwörter

Keywords

Search

Navigation