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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.
- synovitis
- rheumatoid arthritis
- fibroblasts
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Footnotes
Handling editor Josef S Smolen
Contributors TL: concepts and design, experiments, interpretation or results and manuscript writing. MB: designed and conducted some in vivo experiments, interpretation of results and reviewed final manuscript. AL: conducted and designed, conducted and interpreted in vitro experiments with FLS and reviewed final manuscript. EG: assisted with animal breeding and tissue culture and reviewed final manuscript. CH: assisted with animal breeding, tissue culture and conducted invasion, WB and qPCRs, and reviewed final manuscript; PSG: conceptualised and oversaw this project, conducted in vivo experiments, interpreted all data, prepared figures and wrote the manuscript.
Funding Institutional funds.
Competing interests None declared.
Patient consent Not required.
Ethics approval All the experiments with animals were conducted according to a protocol approved by the Feinstein Institute’s animal care and use committee. All RA synovial cell lines were developed from deidentified tissues obtained by the Feinstein Institute Tissue Donation programme under and IRB-approved protocol.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All sequencing data are available on request or via the Rat Genome Database.