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

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.

journal_name

Ann Rheum Dis

authors

Laragione T,Brenner M,Lahiri A,Gao E,Harris C,Gulko PS

doi

10.1136/annrheumdis-2018-213498

subject

Has Abstract

pub_date

2018-11-01 00:00:00

pages

1627-1635

issue

11

eissn

0003-4967

issn

1468-2060

pii

annrheumdis-2018-213498

journal_volume

77

pub_type

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