Background/Purpose:  Cia25/Pia42 is an arthritis severity and joint damage quantitative trait locus on rat chromosome 12 previously identified in an intercross between MHC identical but disease discordant DA (arthritis-susceptible) and ACI (resistant) rats. DA.ACI(Cia25/Pia42) congenic rats were significantly protected in both Pristane and Collagen-induced arthritis (PIA and CIA) compared with DA. This study aimed at positionally identifying the gene accounting for Cia25/Pia42 gene.

Methods: Recombinant subcongenics covering the Cia25/Pia42 interval were generated by backcrossing the original congenic strain with DA using a genotype-guided strategy. Recombinants sharing identical intervals were then intercrossed to homozygozity. PIA was induced in 8-12 week-old subcongenic rats and disease scored for 31 days using a system that correlates with histological damage. Fibroblast-like synoviocytes (FLS) from rats and patients with rheumatoid arthritis (RA) were studied in in vitro invasion assays previously shown to correlate with radiographic damage.

Results:  Analyses of 12 different recombinant (R) subcongenic strains reduced the gene-containing interval from 33Mb to a 1.2MB region contained within subcongenic R6. R6 subcongenics had significantly 92% lower median arthritis severity score compared with DA (P<0.001) and were significantly protected from developing cartilage or bone damage (P<0.002). Sequencing of the 36 genes in the 1.2MB critical interval identified three genes with amino-acid changing SNPs with predicted protein functional consequences based on SIFT and PolyPhen2 analyses. These three genes were expressed in FLS from arthritic rats and patients with rheumatoid arthritis (RA). Huntingtin-interacting protein 1 (Hip1), a gene implicated in clathrin-mediated endocytosis, was one of these genes and was expressed in increased levels in DA FLS compared with R6. FLS from protected DA.ACI(Cia25/Pia42) subcongenic R6 were less invasive than those from DA rats, suggesting that the Cia25/Pia42 gene operates via the regulation of FLS invasion. siRNA Hip1 significantly reduced the invasive properties of FLS obtained from DA rats and from patients with RA. Hip1 knock-out mice were obtained and were protected in KRN serum-induced arthritis, confirming the importance of this gene in arthritis.

Conclusion:  Hip1 is a new arthritis severity and joint damage gene that mediates disease at least in part via the regulation of the invasive properties of FLS. The identification of this new gene is the first step towards developing new therapies and a new prognostic biomarker for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/huntingtin-interacting-protein-1-hip1-is-a-new-arthritis-severity-gene/