Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Burja, Blaž; Mertelj, Tonja; Frank-Bertoncelj, Mojca

doi:10.3389/fmed.2020.00124

Cited by 19 publications

(18 citation statements)

References 83 publications

(107 reference statements)

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“…All three types of interferons signal via the JAK-STAT signalling pathway, which, along with TNF, is one of the central therapeutic targets in RA. IFN pathways are strongly associated with the pathogenesis of RA and IFN-responsive genes are induced in FLS upon stimulation with TNF [ 45 ]. A type I interferon gene signature is detectable in up to two thirds of patients with RA [ 46 ], and it associates with an increased risk of developing RA as well as with therapeutic response to biological DMARDs like TNF inhibitors [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Frank-Bertoncelj

Klein

et al. 2021

Genome Biol

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Background Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci. Results We identify putative causal variants, enhancers, genes, and cell types for 30–60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Conclusion Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

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Section: Discussionmentioning

confidence: 99%

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Frank-Bertoncelj

Klein

et al. 2021

Genome Biol

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“…[ 13 ] In addition, FDA‐approved Janus kinase inhibitors, such as tofacitinib, baricitinib and upadacitinib, can alleviate arthritis by interfering with the migration and invasion of FLS. [ 14 ] The biological anti‐rheumatic drug abatacept inhibits the migration and matrix metalloproteinase expression of FLS by preventing the activation of mitogen‐activated protein kinase signals and thereby delaying the development of RA. [ 15 ] The inhibition of FLS migration and invasion is the mechanism underlying the therapeutic effect of iguratimod, a new anti‐rheumatic drug approved in China and Japan.…”

Section: Introductionmentioning

confidence: 99%

Morin Acts as a USP7 Inhibitor to Hold Back the Migration of Rheumatoid Arthritis Fibroblast‐Like Synoviocytes in a “Prickle1‐mTORC2” Dependent Manner

Yang

Cao

Miao

et al. 2021

Molecular Nutrition Food Res

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Introduction The aim of this study is to investigate the effect and detailed mechanisms of morin, an anti‐arthritis compound widely distributed in foods of plant origin, on the pathological migration of fibroblast‐like synoviocytes (FLS). Methods and Results The migration of FLS collected from arthritis rats and MH7A cells is induced by platelet‐derived growth factor, and an arthritis model in rats is established by Freund's complete adjuvant. The results show that morin remarkably restrains FLS migration but slightly affects FLS apoptosis and proliferation. Moreover, in the progression of FLS migration, focal adhesion (FA) turnover is inhibited by morin via lowering the activation of Paxillin and focal adhesion kinase (FAK) and internalization of integrin β1. Morin disrupts the formation of mTOR complex 2 (mTORC2) and the activation of AKT (S473) and PKCα (S657), and MHY1485 reverses morin‐limited FLS migration. Of note, the protein stability of Prickle1, a binding factor of Rictor, is reduced by morin, and MG132 but not Baf A1 shows a repressive effect. Finally, the target protein is identified as ubiquitin‐specific protease 7 (USP7) but not USP9X. USP7 overexpressing plasmid weakens morin‐affected protein and ubiquitination of Prickle1, and mechanisms are confirmed in vivo by using an overexpressing plasmid and inhibitor. Conclusion Morin restricts FLS migration and arthritis by intervening in “USP7‐Prickle1‐mTORC2” signaling and FA turnover.

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“…IFN pathways are strongly associated with the pathogenesis of RA and IFN-responsive genes are induced in FLS upon stimulation with TNF 27 . The TNFAIP3/IFNGR1 region on chromosome 6 and the IFNAR1/IFNGR2 region on chromosome 21 interacted with genes encoding five subunits of the IFN I/III receptors in FLS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Frank-Bertoncelj

Klein

et al. 2020

Preprint

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Genome-wide association studies have reported >100 risk loci for rheumatoid arthritis (RA). These loci have been shown to be enriched in immune cell-specific enhancers, but analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrated DNA architecture (ChIP-seq), 3D chromatin interactions (HiC, capture HiC), DNA accessibility (ATAC-seq) and gene expression (RNA-seq) in FLS, B cells and T cells with genetic fine mapping of RA loci. We identified putative causal variants, enhancers, genes, and cell types for 30 - 60% of RA loci and demonstrated that FLS account for up to 24% of RA heritability. TNF stimulation of FLS altered the organization of topologically associating domains (TADs), chromatin state and the expression of putative causal genes (e.g. TNFAIP3, IFNAR1). Several putative causal genes constituted RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrated that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA. Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.

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Hi-JAKi-ng Synovial Fibroblasts in Inflammatory Arthritis With JAK Inhibitors

Cited by 19 publications

References 83 publications

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

Morin Acts as a USP7 Inhibitor to Hold Back the Migration of Rheumatoid Arthritis Fibroblast‐Like Synoviocytes in a “Prickle1‐mTORC2” Dependent Manner

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability

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