NR4A2 Expression Patterns in Mouse Models of Rheumatoid Arthritis

Abstract

Arthritis is a group of over 100 musculoskeletal disorders affecting approximately 50 million adults in the US. In an effort to develop new drugs to treat arthritis, we are exploring the function of the orphan nuclear receptor 4A2 (NR4A2), a transcription factor over-expressed in inflamed joints. The transcriptional targets of NR4A2 include angiogenesis factors and matrix metalloproteinases (MMPs). NR4A2 appears to have a deleterious effect in synoviocytes by promoting tissue degradation, while in chondrocytes it seems to have a protective function. Previous work on human synoviocytes has shown NR4A2 to rise early in response to inflammation, leading us to hypothesize that NR4A2 may be a preliminary mediator of arthritis. To test this hypothesis in vivo, we studied NR4A2 expression patterns in two mouse models of RA: Antigen Induced Arthritis (AIA) and Serum Transfer Arthritis (STA). Tissue sections were obtained from healthy and arthritic mice at early, mid, and late time-points following induction. Joint cross-sections were examined via immunohistochemical staining, and NR4A2 positive cells were quantified in synovial and cartilage tissues. In the AIA model, NR4A2 protein levels peaked in synovium at day 10 of disease (mid stage, 50% positive) and declined later in disease. In cartilage, protein levels reached a maximum at day 8 (early stage, 70%) and subsequently declined as well. In contrast, NR4A2 was not expressed in the STA model, despite apparent joint degradation. NR4A2 has been shown to be expressed in STA arthritis by other researchers, so it is unknown why STA samples did not show NR4A2 expression in our experiment.