Abstract
Abstract Molecular mechanisms of sex disparities in autoimmune inflammatory diseases, including rheumatoid arthritis (RA), are not well defined. To model human disease, collagen antibody-induced arthritis (CAIA) was induced in BALB/c.DBA/2-Pgia8 congenic mice. Chromosome interval Pgia8 showed anti-inflammatory effect in congenic males, while females exhibited CAIA that was similar to wild-type mice. Transcriptome analysis indicated that expression of three locus-specific genes was tightly correlated (r=0.87-0.91) with inflammation: Collagen triple helix repeat containing 1 (Cthrc1), R-spondyn 2 and Syndecan 2. The link between Cthrc1 and arthritis was reproduced in F1(BALB/c x FVB-Tg[Cthrc1]) mice, since mice overexpressing Cthrc1 transgene showed 1.2-1.4-fold stronger inflammation than tg-negative F1 hybrids. Importantly, naïve F1(BALB/c x FVB-Tg[Cthrc1]) mice exhibited pre-inflammatory phenotype of neutrophilia (30% upregulated, p<0.014) accompanied with monocytopenia (50% downregulated, p<0.025) in peripheral blood. Cellular mechanisms of arthritis regulation via Cthrc1 were addressed using immunodetection techniques. Present study indicates that promigratory protein Cthrc1 effects hematopoiesis and is also implicated in sex-biased regulation of inflammatory arthritis.
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