Citrullination of synovial proteins in murine models of rheumatoid arthritis

Antibodies directed to citrulline-containing proteins are highly specific for rheumatoid arthritis (RA) and can be detected in up to 80% of RA patients. Citrulline is an unnatural amino acid that can be incorporated into proteins only by post-translational modification of arginine by peptidylarginine deiminase (PAD) enzymes. We investigated the presence of anticitrulline antibodies, PAD enzymes and citrullinated antigens in an acute and a chronic destructive mouse model for arthritis: streptococcal-cell-wall arthritis and collagen-induced arthritis. In both mouse models, PAD2 mRNA is present in the synovium but not translated into PAD2 protein. In contrast, PAD4 mRNA, although absent from healthy synovia, is readily transcribed and translated by polymorphonuclear neutrophils infiltrating the synovial tissue during inflammation. As a consequence, several synovial proteins are subjected to citrullination. One of these proteins was identified as fibrin, which has been reported to be citrullinated also in the synovia of RA patients. Although the generation of citrullinated antigens during synovial inflammation in the mice was eminent, no anticitrullinated protein antibodies could be detected. In conclusion, the citrullination of synovial antigens is an active process during joint inflammation both in mouse and man, but the induction of autoantibodies directed against these proteins is a more specific phenomenon detectable only in RA patients.