Faculty Opinions recommendation of Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation.

Abstract Objective Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using 68Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. Methods Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received 68Ga-FAPI-04 and was scanned using PET/CT imaging. Results In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. Conclusion In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.

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Splicing machinery is impaired in rheumatoid arthritis, associated with disease activity and modulated by anti-TNF therapy

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-220308 ◽

2021 ◽

pp. annrheumdis-2021-220308

Author(s):

Alejandro Ibáñez-Costa ◽

Carlos Perez-Sanchez ◽

Alejandra María Patiño-Trives ◽

Maria Luque-Tevar ◽

Pilar Font ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Fluid ◽

Disease Activity ◽

Synovial Fibroblasts ◽

Data Set ◽

Altered Expression ◽

Healthy Donors ◽

Inflammatory Profile ◽

Splicing Machinery

ObjectivesTo characterise splicing machinery (SM) alterations in leucocytes of patients with rheumatoid arthritis (RA), and to assess its influence on their clinical profile and therapeutic response.MethodsLeucocyte subtypes from 129 patients with RA and 29 healthy donors (HD) were purified, and 45 selected SM elements (SME) were evaluated by quantitative PCR-array based on microfluidic technology (Fluidigm). Modulation by anti-tumour necrosis factor (TNF) therapy and underlying regulatory mechanisms were assessed.ResultsAn altered expression of several SME was found in RA leucocytes. Eight elements (SNRNP70, SNRNP200, U2AF2, RNU4ATAC, RBM3, RBM17, KHDRBS1 and SRSF10) were equally altered in all leucocytes subtypes. Logistic regressions revealed that this signature might: discriminate RA and HD, and anti-citrullinated protein antibodies (ACPAs) positivity; classify high-disease activity (disease activity score-28 (DAS28) >5.1); recognise radiological involvement; and identify patients showing atheroma plaques. Furthermore, this signature was altered in RA synovial fluid and ankle joints of K/BxN-arthritic mice. An available RNA-seq data set enabled to validate data and identified distinctive splicing events and splicing variants among patients with RA expressing high and low SME levels. 3 and 6 months anti-TNF therapy reversed their expression in parallel to the reduction of the inflammatory profile. In vitro, ACPAs modulated SME, at least partially, by Fc Receptor (FcR)-dependent mechanisms. Key inflammatory cytokines further altered SME. Lastly, induced SNRNP70-overexpression and KHDRBS1-overexpression reversed inflammation in lymphocytes, NETosis in neutrophils and adhesion in RA monocytes and influenced activity of RA synovial fibroblasts.ConclusionsOverall, we have characterised for the first time a signature comprising eight dysregulated SME in RA leucocytes from both peripheral blood and synovial fluid, linked to disease pathophysiology, modulated by ACPAs and reversed by anti-TNF therapy.

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Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis

Arthritis & Rheumatism ◽

10.1002/art.23386 ◽

2008 ◽

Vol 58 (4) ◽

pp. 1001-1009 ◽

Cited By ~ 562

Author(s):

Joanna Stanczyk ◽

Deena M. Leslie Pedrioli ◽

Fabia Brentano ◽

Olga Sanchez-Pernaute ◽

Christoph Kolling ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Synovial Tissue ◽

Synovial Fibroblasts ◽

Altered Expression

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Inhibition of PCSK6 May Play a Protective Role in the Development of Rheumatoid Arthritis

The Journal of Rheumatology ◽

10.3899/jrheum.140435 ◽

2014 ◽

Vol 42 (2) ◽

pp. 161-169 ◽

Cited By ~ 9

Author(s):

Feifei Wang ◽

Lin Wang ◽

Huiyu Jiang ◽

Xiaotian Chang ◽

Jihong Pan

Keyword(s):

Rheumatoid Arthritis ◽

Expression Profiles ◽

Synovial Fibroblasts ◽

Protective Role ◽

Taqman Probe ◽

G1 Arrest ◽

Healthy Controls ◽

Altered Expression ◽

Synovial Tissues ◽

Factor Α

Objective.To assess the effect of proprotein convertase subtilisin/kexin type 6 (PCSK6) in the synovial fibroblasts of rheumatoid arthritis (RA). PCSK6 is a proteinase implicated in the proteolytic activity of various precursor proteins and involved in the regulation of protein maturation.Methods.PCSK6 expression was detected in the synovial tissue of 10 patients with RA, 10 controls with osteoarthritis, and 10 controls with ankylosing spondylitis using Western blotting and quantitative real-time PCR. Genotyping of 67 tag single-nucleotide polymorphisms (SNP) was performed using an Illumina VeraCode (Illumina) microarray in a case-control study including 267 patients with RA and 160 healthy controls. Genotyping of 4 other tag SNP was performed using a TaqMan probe genotyping assay in 1056 healthy controls and 1151 patients with RA. Cultured RA synovial fibroblasts (RASF) were transfected with PCSK6 small interfering RNA to study changes in the proliferation, invasion, migration capacity, secretion of inflammatory cytokines, cell cycle, and expression profiles of the RASF.Results.Expression of PCSK6 mRNA and protein was significantly higher in the synovial tissues of individuals with RA than in control tissues. One SNP, rs8029797, was significantly associated with RA (p = 0.011). Knockdown of PCSK6 by RNA interference significantly decreased proliferation, invasion, and migration of RASF. These changes in RASF appeared to be related to reduced tumor necrosis factor-α secretion, G0/G1 arrest, and altered expression of various proteins including those involved in angiogenesis (matrix metalloproteinase 9, nitric oxide synthase trafficking), hypoxia (hypoxia-inducible factor-α, thioredoxin domain containing 5), proliferation (chromosome 10 open reading frame 116), and inflammation [CCL7, chemokine (C-X-C motif) ligand 9, interleukin 26].Conclusion.PCSK6 is upregulated in the synovial tissues of patients with RA and has a genetic effect on the risk of RA. Inhibition of PCSK6 may play a protective role in the development of RA.

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