Wnt signaling genes of murine chromosome 15 are involved in sex‐affected pathways of inflammatory arthritis

Abstract

Objective Sex disparities in rheumatoid arthritis (RA) are well documented despite the lack of any known major RA susceptibility genes mapped to sex chromosomes. Murine chromosome 15 carries the sex‐affected Pgia8 locus that mediates proteoglycan‐induced arthritis, and homologous human loci are associated with RA. This study was undertaken to identify genes/mechanisms implicated in sex disparities in arthritis. Methods Gene expression analysis was performed using RNA isolated from the paws of male and female Pgia8‐congenic mice with collagen antibody–induced arthritis. Results were corroborated by reverse transcription–polymerase chain reaction, and mice were also studied prior to disease onset. Ingenuity Pathways Analysis of the expression patterns and gene functions was used to discover locus‐specific and sex‐affected signature transcripts. Results We found that the Pgia8 locus regulates antibody‐mediated inflammatory arthritis differently in males and females. In Pgia8‐congenic males, arthritis severity was 30% less (P < 0.005) than in wild‐type males, but the antiinflammatory effect was similar in wild‐type and congenic females. Transcriptome analysis indicated that 12 genes within the locus were significantly dysregulated in arthritic joints of congenic mice; expression of these genes was also sex specific. The genes that correlated most highly with arthritis severity included those for collagen triple‐helix repeat–containing 1 (Cthrc1), metalloproteinase (Adamts12), R‐spondin (Rspo2), and syndecan (Sdc2) (r = 0.87–0.91). The level of Cthrc1 message also correlated with that of the genes for the proinflammatory cytokines interleukin‐1β and interleukin‐6. Conclusion These results indicate that sex‐specific disparities in RA are linked to transcriptional regulation of genes involved in cartilage degradation (Adamts12) and canonical and noncanonical Wnt signaling (Cthrc1, Rspo2, Sdc2).