Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling

Teresina Laragione, Max Brenner, Amit Lahiri, Erjing Gao, Carolyn Harris, Percio S. Gulko

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Objectives While new treatments for rheumatoid arthritis (RA) have markedly improved disease control by targeting immune/inflammatory pathways, current treatments rarely induce remission, underscoring the need for therapies that target other aspects of the disease. Little is known about the regulation of disease severity and joint damage, which are major predictors of disease outcome, and might be better or complementary targets for therapy. In this study, we aimed to discover and characterise a new arthritis severity gene. Methods An unbiased and phenotype-driven strategy including studies of unique congenic rat strains was used to identify new arthritis severity and joint damage genes. Fibroblast-like synoviocytes (FLS) from rats and patients with RA expressing or not Huntingtin-interacting protein 1 (HIP1) were studied for invasiveness, morphology and cell signalling. HIP1 knockout mice were used in in vivo confirmatory studies. Paired t-test was used. Results DNA sequencing and subcongenic strains studied in pristane-induced arthritis identified a new amino acid changing functional variant in HIP1. HIP1 was required for the increased invasiveness of FLS from arthritic rats and from patients with RA. Knocking down HIP1 expression reduced receptor tyrosine kinase-mediated responses in RA FLS, including RAC1 activation, affecting actin cytoskeleton and cell morphology and interfering with the formation of lamellipodia, consistent with reduced invasiveness. HIP1 knockout mice were protected in KRN serum-induced arthritis and developed milder disease. Conclusion HIP1 is a new arthritis severity gene and a potential novel prognostic biomarker and target for therapy in RA.

Original languageEnglish
Pages (from-to)1627-1635
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume77
Issue number11
DOIs
StatePublished - 1 Nov 2018

Keywords

  • fibroblasts
  • rheumatoid arthritis
  • synovitis

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