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

Nature Clinical Practice Rheumatology volume 1, pages 102–110 (2005)Cite this article

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

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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.

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Acknowledgements

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

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Authors and Affiliations

  1. Department of Internal Medicine and Rheumatology, Justus-Liebig University Giessen, Kerckhoff-Clinic, Bad Nauheim, Germany

    Ulf Müller-Ladner & Thomas Pap

  2. Division of Molecular Medicine of Musculoskeletal Tissue, Department of Orthopedics, University Hospital of Münster, Germany

    Ulf Müller-Ladner & Thomas Pap

  3. Department of Rheumatology, at the University Hospital and Center for Integrative Human Physiology (CIHP), Zürich, Switzerland

    Renate E Gay, Michel Neidhart & Steffen Gay

  4. Department of Rheumatology, Center of Experimental Rheumatology, University Hospital, Zürich, Switzerland

    Renate E Gay, Michel Neidhart & Steffen Gay

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  1. Ulf Müller-Ladner
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  2. Thomas Pap
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Correspondence to Steffen Gay.

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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

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