Abstract
A better understanding of the initial mechanisms that lead to arthritic disease could facilitate development of improved therapeutic strategies. We characterized the synovial microcirculation of knee joints in susceptible mouse strains undergoing intradermal immunization with bovine collagen II in complete Freund's adjuvant to induce arthritis (i.e. collagen-induced arthritis [CIA]). Susceptible DBA1/J and collagen II T-cell receptor transgenic mice were compared with CIA-resistant FVB/NJ mice. Before onset of clinical symptoms of arthritis, in vivo fluorescence microscopy of knee joints revealed marked leucocyte activation and interaction with the endothelial lining of synovial microvessels. This initial inflammatory cell response correlated with the gene expression profile at this disease stage. The majority of the 655 differentially expressed genes belonged to classes of genes that are involved in cell movement and structure, cell cycle and signal transduction, as well as transcription, protein synthesis and metabolism. However, 24 adhesion molecules and chemokine/cytokine genes were identified, some of which are known to contribute to arthritis (e.g. CD44 and neutrophil cytosolic factor 1) and some of which are novel in this respect (e.g. CC chemokine ligand-27 and IL-13 receptor α1). Online in vivo data on synovial tissue microcirculation, together with gene expression profiling, emphasize the potential role played by early inflammatory events in the development of arthritis.
Highlights
Murine collagen-induced arthritis (CIA) is a chronic inflammatory disease that bears all the hallmarks of rheumatoid arthritis (RA), namely polyarthritis and synovitis with subsequent cartilage and bone erosions [1]
Intravital fluorescence microscopy of the knee joints was performed at 6 weeks after collagen exposure for induction of arthritis
In the present study we found that susceptible mice that were exposed to complete Freund's adjuvant (CFA)/collagen II for induction of arthritis exhibited marked signs of inflammation within the microcirculation of the knee joint, animals were still free from clinical symptoms
Summary
Murine collagen-induced arthritis (CIA) is a chronic inflammatory disease that bears all the hallmarks of rheumatoid arthritis (RA), namely polyarthritis and synovitis with subsequent cartilage and bone erosions [1]. The development of CIA is thought to depend on T cells, and disease susceptibility is linked to the major histocompatibility region [2]. Activated lymphocytes migrate to the joint, where an inflammatory cascade involving T cells, macrophages, monocytes, B cells and activated synoviocytes is triggered. This cellular infiltration, together with production of a complex array of cytokines and other soluble mediators, contributes to synovial proliferation, pannus formation, cartilage destruction and subchondral bone erosion [3]. The technique of intravital fluorescence microscopy permits dissection of the complex cell inflammatory response, with differentiation between cellular subtypes and their distinct adhesion molecule dependent interactions within the microcirculation
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