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Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs

Thomas Häupl¹, Mehdi Yahyawi, Carsten Lübke

¹Tissue Engineering Laboratory, Department of Rheumatology, Charité-Universitätsmedizin Berlin, Campus Mitte, Tucholskystrasse 2, 10117 Berlin, Germany. thomas.haeupl@charite.de

Journal of Biomolecular Screening

|March 24, 2007

Abstract:

Nonbiological therapeutics are frequently used for the treatment of patients with rheumatoid arthritis (RA). Because the mechanisms of action of these therapeutics are unclear, the authors aimed to elucidate the molecular effects of typical antirheumatic drugs on the expression profile of RA-related genes expressed in activated synovial fibroblasts. For reasons of standardization and comparability, immortalized synovial fibroblasts derived from RA (RASF) and normal donors (NDSF) were treated with methotrexate, prednisolone, or diclofenac and used for gene expression profiling with oligonucleotide microarrays. The cytotoxicity of the antirheumatic drugs was tested in different concentrations by MTS tetrazolium assay. Genes that were differentially expressed in RASF compared to NDSF and reverted by treatment with antirheumatic drugs were verified by semiquantitative polymerase chain reaction and by chemiluminescent enzyme immunoassay. Treatment with methotrexate resulted in the reversion of the RA-related expression profile of genes associated with growth and apoptosis including insulin-like growth factor binding protein 3, retinoic acid induced 3, and caveolin 2 as well as in the re-expression of the cell adhesion molecule integrin alpha6. Prednisolone reverted the RA-related profile of genes that are known from inflammation and suppressed interleukins 1beta and 8. Low or high doses of diclofenac had no effect on the expression profile of genes related to RA in synovial fibroblasts. These data give the first insight into the mechanisms of action of common antirheumatic drugs used for the treatment of arthritides. Synovial fibroblasts reflect the disease-related pathophysiology and are useful tools for screening putative antirheumatic compounds.

Insights

Methotrexate and prednisolone alter rheumatoid arthritis (RA) gene expression in synovial fibroblasts, offering insights into antirheumatic drug mechanisms. Diclofenac showed no significant effect on RA-related gene profiles.

Area of Science:

Rheumatology
Molecular Biology
Pharmacology

Background:

Rheumatoid arthritis (RA) treatment often involves non-biological drugs with unclear molecular mechanisms.
Understanding these mechanisms is crucial for optimizing RA therapy.

Purpose of the Study:

To investigate the molecular effects of common antirheumatic drugs on gene expression profiles in rheumatoid arthritis synovial fibroblasts (RASF).
To elucidate the mechanisms of action for methotrexate, prednisolone, and diclofenac in the context of RA.

Main Methods:

Gene expression profiling using oligonucleotide microarrays on immortalized RASF and normal donor synovial fibroblasts (NDSF).
Treatment with methotrexate, prednisolone, and diclofenac.
Cytotoxicity assessment via MTS assay.
Verification of differentially expressed genes using polymerase chain reaction and enzyme immunoassay.

Main Results:

Methotrexate reverted RA-related gene expression profiles associated with growth and apoptosis, and re-expressed cell adhesion molecules.
Prednisolone modulated inflammation-related genes and suppressed interleukin-1beta and -8.
Diclofenac demonstrated no significant effect on RA-related gene expression in synovial fibroblasts.

Conclusions:

This study provides initial insights into the molecular mechanisms of common antirheumatic drugs.
Synovial fibroblasts are valuable models for studying RA pathophysiology and screening new antirheumatic compounds.

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