Adenosine receptor expression in rheumatoid synovium: a basis for methotrexate action

Area of Science:

• Rheumatology
• Pharmacology
• Molecular Biology

Background:

• Methotrexate (MTX) is a key therapy for rheumatoid arthritis (RA), with anti-inflammatory effects partly mediated by adenosine receptors (ADOR).
• Understanding ADOR expression in RA synovium and MTX's influence is crucial for optimizing RA treatment.
• Investigating ADORA3 gene polymorphisms may reveal links to MTX efficacy and side effects.

Purpose of the Study:

• To determine the expression of all four adenosine receptor genes in rheumatoid arthritis synovial tissue.
• To assess the impact of MTX exposure on adenosine receptor gene expression.
• To investigate the association between ADORA3 gene polymorphisms and MTX response or adverse effects in RA patients.

Main Methods:

• Adenosine receptor gene expression analysis using PCR on 20 RA synovial samples.
• Genotyping of 225 RA patients on MTX for ADORA3 single nucleotide polymorphisms (SNPs).
• Double immunofluorescence to identify cells expressing ADOR protein.

Main Results:

• All adenosine receptor genes were expressed in RA synovial tissue; ADORA3 and its variant were dominant.
• MTX therapy correlated with increased expression of ADORA2A and ADORA2B genes.
• No association was found between the ADORA3 rs1544224 SNP and disease activity or MTX adverse effects.
• ADORA2B protein was mainly in vascular endothelial cells, while ADORA3 protein was abundant in synovial fibroblasts.

Conclusions:

• Adenosine receptors are expressed in RA synovium, with ADORA3 being significantly upregulated.
• Differential expression of ADOR subtypes in RA synovium highlights potential therapeutic targets.
• Findings support the hypothesis that MTX exerts anti-inflammatory effects directly within the RA joint via adenosine receptors.