Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis

Abstract

Rheumatoid arthritis is a complex systemic disease that ultimately leads to the progressive destruction of articular and periarticular structures. Novel data indicate that the innate immune system (through activation of Toll-like receptors) is involved in articular pathophysiology, including the recruitment of inflammatory cells, and that periarticular factors such as adipocytokines contribute to the perpetuation of joint inflammation. The deleterious process of joint destruction is mediated by intracellular signaling pathways involving transcription factors, such as nuclear factor κB, cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules. Advances in molecular biology techniques have identified T-cell-independent and B-cell-independent pathways that operate at different stages of the disease. Cytokine-independent pathways appear to be responsible for maintaining basic disease activity that is not affected by currently available therapies. Using this knowledge in combination with gene-transfer and gene-silencing approaches, bench-to-bedside strategies will be developed, thus enabling the creation of novel treatments for rheumatoid arthritis.

Key Points

  • Molecular biology has unveiled numerous steps in the pathophysiology of rheumatoid arthritis, including pathways of cellular activation, inflammation, adhesion, and matrix degradation

  • The innate immune system is centrally involved in articular pathophysiology via Toll-like receptor signaling by macrophages, dendritic cells, and fibroblasts, which subsequently leads to the early recruitment of inflammatory cells

  • The deleterious process of joint destruction is mediated by activation of intracellular signaling pathways and leads to the production of cytokines, chemokines, growth factors, cellular ligands, and adhesion molecules

  • Periarticular factors, such as adipocytokines, can contribute to the perpetuation of joint inflammation and enhance the destructive potential of matrix-degrading synovial fibroblasts

  • Cytokine-independent pathways mediated by activated synovial fibroblasts appear to be responsible for maintaining persistent disease activity that is not affected by currently available therapies

  • T-cell-independent and B-cell-independent pathways that are operative at different stages of the disease can be targeted therapeutically by gene-transfer and gene-silencing approaches

This is a preview of subscription content, access via your institution

Access options

Buy this article

Purchase on Springer Link

Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pathways involved in inflammation and destruction in the rheumatoid joint.
Figure 2: Induction of proinflammatory cytokines, matrix-degrading enzymes, and chemokines in Toll-like receptor-2-expressing RASF at sites of invasion into the adjacent cartilage following stimulation with lipopolysaccharides and bacterial peptidoglycans.
Figure 3: Activation of different pathways in the course of rheumatoid joint destruction.

Similar content being viewed by others

References

  1. Neumann E et al. (2002) Identification of differentially expressed genes in rheumatoid arthritis by a combination of complementary DNA array and RNA arbitrarily primed-polymerase chain reaction. Arthritis Rheum 46: 52–63

    Article  CAS  Google Scholar 

  2. Faour WH et al. (2005) Early growth response factor-1 mediates prostaglandin E2-dependent transcriptional suppression of cytokine-induced tumor necrosis factor-α gene expression in human macrophages and rheumatoid arthritis-affected synovial fibroblasts. J Biol Chem 280: 9536–9546

    Article  CAS  Google Scholar 

  3. Garcia-Vicuna R et al. (2004) CC and CXC chemokine receptors mediate migration, proliferation, and matrix metalloproteinase production by fibroblast-like synoviocytes from rheumatoid arthritis patients. Arthritis Rheum 50: 3866–3877

    Article  CAS  Google Scholar 

  4. Kasperkovitz PV et al. (2005) Fibroblast-like synoviocytes derived from patients with rheumatoid arthritis show the imprint of synovial tissue heterogeneity: evidence of a link between an increased myofibroblast-like phenotype and high-inflammation synovitis. Arthritis Rheum 52: 430–441

    Article  Google Scholar 

  5. Firestein GS (2003) Evolving concepts of rheumatoid arthritis. Nature 423: 356–361

    Article  CAS  Google Scholar 

  6. Ferrari-Lacraz S et al. (2004) Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J Immunol 173: 5818–5826

    Article  CAS  Google Scholar 

  7. Miranda-Carus ME et al. (2004) IL-15 and the initiation of cell contact-dependent synovial fibroblast-T lymphocyte cross-talk in rheumatoid arthritis: effect of methotrexate. J Immunol 173: 1463–1476

    Article  CAS  Google Scholar 

  8. Neumann E et al. (2005) The RANK/RANKL/OPG system in rheumatoid arthritis: new insights from animal models. Arthritis Rheum 52: 2960–2967

    Article  CAS  Google Scholar 

  9. Schmutz C et al. (2005) Chemokine receptors in the rheumatoid synovium: upregulation of CXCR5. Arthritis Res Ther 7: R217–R229

    Article  CAS  Google Scholar 

  10. Takemura S et al. (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167: 1072–1080

    Article  CAS  Google Scholar 

  11. Zheng B et al. (2005) CXCL13 neutralization reduces the severity of collagen-induced arthritis. Arthritis Rheum 52: 620–626

    Article  CAS  Google Scholar 

  12. Van der Voort R et al. (2005) Elevated CXCL16 expression by synovial macrophages recruits memory T cells into rheumatoid joints. Arthritis Rheum 52: 1381–1391

    Article  CAS  Google Scholar 

  13. Franz JK et al. (1998) Interleukin-16 produced by synovial fibroblasts mediates chemoattraction to CD4+ T-cells in rheumatoid arthritis. Eur J Immunol 28: 2661–2671

    Article  CAS  Google Scholar 

  14. Sawai H et al. (2005) T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum 52: 1392–1401

    Article  CAS  Google Scholar 

  15. Ohata J et al. (2005) Fibroblast-like synoviocytes of mesenchymal origin express functional B cell-activating factor of the TNF family in response to proinflammatory cytokines. J Immunol 174: 864–870

    Article  CAS  Google Scholar 

  16. Tarner IH et al. (2005) The different stages of synovitis: acute vs chronic, early vs late and non-erosive vs erosive. Best Pract Res Clin Rheumatol 19: 19–35

    Article  Google Scholar 

  17. Bijlsma JW et al. (2005) Clinical aspects of immune neuroendocrine mechanism in rheumatic diseases. Rheum Dis Clin North Am 31: xiii–xvi

    Article  Google Scholar 

  18. Zeisel MB et al. (2005) MMP-3 expression and release by rheumatoid arthritis fibroblast-like synoviocytes induced with a bacterial ligand of integrin α5β1. Arthritis Res Ther 7: R118–R126

    Article  CAS  Google Scholar 

  19. Seibl R et al. (2004) Expression and regulation of Toll-like receptor 2 in rheumatoid arthritis synovium. Am J Pathol 162: 1221–1227

    Article  Google Scholar 

  20. Pierer M et al. (2004) Chemokine secretion of rheumatoid arthritis synovial fibroblasts stimulated by Toll-like receptor 2 ligands. J Immunol 172: 1256–1265

    Article  CAS  Google Scholar 

  21. Roelofs MF et al. (2005) The expression of toll-like receptors 3 and 7 in rheumatoid arthritis synovium is increased and costimulation of toll-like receptors 3, 4, and 7/8 results in synergistic cytokine production by dendritic cells. Arthritis Rheum 52: 2313–2322

    Article  CAS  Google Scholar 

  22. Neidhart M et al. (2000) Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum 43: 2634–2447

    Article  CAS  Google Scholar 

  23. Ospelt C et al. (2004) Toll-like receptors in rheumatoid arthritis joint destruction mediated by two distinct pathways. Ann Rheum Dis 63 (Suppl II): ii90–ii91

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kurowska M 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

    Article  CAS  Google Scholar 

  25. Schedel J 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  CAS  Google Scholar 

  26. Amano T et al. (2003) Synoviolin/Hrd1, an ubiquitin ligase, as a novel pathogenic factor for arthropathy. Genes Dev 17: 2436–2449

    Article  CAS  Google Scholar 

  27. Franz JK et al. (2000) Expressions of sentrin, a novel anti-apoptopic molecule at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43: 544–607

    Article  Google Scholar 

  28. Miyashita T et al. (2004) Osteoprotegerin (OPG) acts as an endogenous decoy receptor in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of fibroblast-like synovial cells. Clin Exp Immunol 137: 430–436

    Article  CAS  Google Scholar 

  29. Schedel J et al. (2004) Discrepancy between mRNA and protein expression of tumour suppressor maspin in synovial tissue may contribute to synovial hyperplasia in rheumatoid arthritis. Ann Rheum Dis 63: 1205–1211

    Article  CAS  Google Scholar 

  30. Pap T et al. (2000) Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2: 59–64

    Article  CAS  Google Scholar 

  31. Distler JH et al. (2005) The induction of matrix metalloproteinase and cytokine expression in synovial fibroblasts stimulated with immune cells microparticles. Proc Natl Acad Sci USA 102: 2892–2897

    Article  CAS  Google Scholar 

  32. Smolen JS et al. (2003) Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov 2: 473–488

    Article  CAS  Google Scholar 

  33. Müller-Ladner U et al. (1997) Expression of alternatively spliced CS-1 fibronectin isoform and its counter-receptor VLA-4 in rheumatoid arthritis synovium. J Rheumatol 24: 1873–1880

    PubMed  Google Scholar 

  34. Johnston A et al. (2005) The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 114: 154–163

    Article  CAS  Google Scholar 

  35. Valencia X et al. (2004) Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J Exp Med 200: 1673–1679

    Article  CAS  Google Scholar 

  36. Neidhart M et al. (1999) Synovial fluid CD146 (MUC18) a marker for synovial membrane angiogenesis in rheumatoid arthritis. Arthritis Rheum 42: 622–630

    Article  CAS  Google Scholar 

  37. Giatromanolaki A et al. (2001) The angiogenic pathway 'vascular endothelial growth factor/flk-1(KDR)-receptor' in rheumatoid arthritis and osteoarthritis. J Pathol 194: 101–108

    Article  CAS  Google Scholar 

  38. Afuwape AO et al. (2003) Adenoviral delivery of soluble VEGF receptor 1 (sFlt-1) abrogates disease activity in murine collagen-induced arthritis. Gene Ther 10: 1950–1960

    Article  CAS  Google Scholar 

  39. Nakahara H et al. (2003) Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum 48: 1521–1529

    Article  CAS  Google Scholar 

  40. Park YW et al. (2004) Thrombospondin 2 functions as an endogenous regulator of angiogenesis and inflammation in rheumatoid arthritis. Am J Pathol 165: 2087–2098

    Article  CAS  Google Scholar 

  41. Takahara K et al. (2004) Autocrine/paracrine role of the angiopoietin-1 and -2 /Tie2 system in cell proliferation and chemotaxis of cultured fibroblastic synoviocytes in rheumatoid arthritis. Hum Pathol 35: 150–158

    Article  CAS  Google Scholar 

  42. Pap T et al. (2000) Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Arthritis Rheum 43: 1226–1232

    Article  CAS  Google Scholar 

  43. Judex MO and Mueller BM (2005) Plasminogen activation/plasmin in rheumatoid arthritis: matrix degradation and more. Am J Pathol 166: 645–647

    Article  Google Scholar 

  44. Yang YH et al. (2005) Reduction of arthritis severity in protease-activated receptor-deficient mice. Arthritis Rheum 52: 1325–1332

    Article  CAS  Google Scholar 

  45. Schäffler A et al. (2003) Adipocytokines in synovial fluid. JAMA 290: 1709–1710

    Article  Google Scholar 

  46. Bokarewa M et al. (2005) Resistin, an adipokine with potent proinflammatory properties. J Immunol 174: 5789–5795

    Article  CAS  Google Scholar 

  47. Van Lent P et al. (2005) Expression of the novel metalloproteinase inhibitor RECK (reversion inducing cysteine-rich protein with Kazal motifs) in inflamed membranes of rheumatoid arthritis patients. Ann Rheum Dis 64: 368–374

    Article  CAS  Google Scholar 

  48. Fassbender HG et al. (1980) Transformation of synovial cells in rheumatoid arthritis. Verh Dtsch Ges Pathol 64: 193–212

    CAS  PubMed  Google Scholar 

  49. Gay S et al. (1993) Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction? Ann Rheum Dis 52 (Suppl 1): S39–S47

    Article  Google Scholar 

  50. Neidhart M et al. (2005). Galectin-3 is induced in rheumatoid arthritis synovial fibroblasts after adhesion to cartilage oligomeric matrix protein. Ann Rheum Dis 64: 419–424

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The work is funded, in part, by grants from the German Research Society (DFG) and the Swiss National Fund.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Steffen Gay.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Müller-Ladner, U., Pap, T., Gay, R. et al. Mechanisms of Disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Rev Rheumatol 1, 102–110 (2005). https://doi.org/10.1038/ncprheum0047

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0047

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing