title: 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.
  
  
  CONCLUSIONS
  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).
authors: Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors: Elena
authors: E
authors: Kudryavtseva
authors: Toni S
authors: TS
authors: Forde
authors: Andrew D
authors: AD
authors: Pucker
authors: Vyacheslav A
authors: VA
authors: Adarichev
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D051379:Mice; D012720:Severity of Illness Index; D012737:Sex Factors; D060449:Wnt Signaling Pathway / Q000235:genetics*