Genome-wide association study of inbred murine strains discovered nuclear factor of activated T-cells Nfatc4 as a major gene controlling severity of inflammatory arthritis. (47.14)

Abstract

Abstract Nuclear factor of activated T cells (NFAT) is a family of transcription factors critical in regulating gene expression in development and disease. NFAT is an important target for cyclosporine immunosuppression in transplant rejection. The NFAT pathway is also important in inflammatory and autoimmune diseases such as rheumatoid arthritis. Using genome-wide association study (GWAS) of antibody-mediated arthritis in inbred murine strains, we found NFATc4 within the major arthritis severity peak at 56.35-56.46 Mb of chromosome 14 with genetic association of log(1/p) > 5.5. To confirm the genetic linkage and functional significance of the NFATc4 gene, we performed collagen antibody-induced arthritis (CAIA) and found that NFATc4-deficient mice exhibited significantly reduced inflammation as compared to wild-type counterparts (55% downregulation, p < 0.01). Immunoblotting analysis demonstrated the presence of NFATc4 in articular cartilage and chondrocytes derived from femoral heads of arthritic and naïve mice. Notably, NFATc4 in chondrocytes isolated from arthritic mice was hypo-phosphorylated as compared to naïve cells, indicating activation of NFATc4. NFATc4, as expected, was not found in splenocytes. We also performed genome-wide Affymetrix oligonucleotide array studies in CAIA experimental arthritis model using wild type and NFATc4-deficient mice. Taking together, we uncovered a novel role of NFATc4 in inflammatory arthritis in chondrocytes.