International Journal of Molecular Sciences

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17 pages, 2229 KiB

Open AccessArticle

14-3-3η Promotes Invadosome Formation via the FOXO3–Snail Axis in Rheumatoid Arthritis Fibroblast-like Synoviocytes

by Maleck Kadiri, Martine Charbonneau, Catherine Lalanne, Kelly Harper, Frédéric Balg, Anthony Marotta and Claire M. Dubois

Int. J. Mol. Sci. 2022, 23(1), 123; https://doi.org/10.3390/ijms23010123 - 23 Dec 2021

Cited by 5 | Viewed by 3118

Abstract

Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the [...] Read more.

Erosive destruction of joint structures is a critical event in the progression of rheumatoid arthritis (RA), in which fibroblast-like synoviocytes (FLS) are the primary effectors. We previously reported that the ability of RA FLS to degrade extracellular matrix (ECM) components depends on the formation of actin-rich membrane protrusions, called invadosomes, through processes that remain elusive. 14-3-3η belongs to a family of scaffolding proteins involved in a wide range of cellular functions, and its expression is closely related to joint damage and disease activity in RA patients. In this study, we sought to assess the role of 14-3-3η in joint damage by examining its contribution to the invadosome formation phenotype of FLS. Using human primary FLS, we show that 14-3-3η expression is closely associated with their ability to form invadosomes. Furthermore, knockdown of 14-3-3η using shRNAs decreases the level of invadosome formation in RA FLS, whereas addition of the recombinant protein to FLS from healthy individuals promotes their formation. Mechanistic studies suggest that 14-3-3η regulates invadosome formation by increasing Snail expression, a mechanism that involves nuclear exclusion of the transcription repressor FOXO3. Our results implicate the 14-3-3η–FOXO3–Snail axis in promoting the aggressive ECM-degrading phenotype of RA FLS, and suggest a role for this scaffolding protein in cartilage degradation. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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13 pages, 2106 KiB

Open AccessArticle

Specific Increase in Joint Neutrophil Extracellular Traps and Its Relation to Interleukin 6 in Autoimmune Arthritis

by Ayako Ohyama, Atsumu Osada, Hoshimi Kawaguchi, Izumi Kurata, Taihei Nishiyama, Tamaki Iwai, Akihito Ishigami, Yuya Kondo, Hiroto Tsuboi, Takayuki Sumida and Isao Matsumoto

Int. J. Mol. Sci. 2021, 22(14), 7633; https://doi.org/10.3390/ijms22147633 - 16 Jul 2021

Cited by 8 | Viewed by 2897

Abstract

Neutrophils and their extracellular traps have been shown to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the detailed mechanisms in joints are still unclear, and their regulation remains to be solved. Here, we explored neutrophil extracellular trap (NET)osis [...] Read more.

Neutrophils and their extracellular traps have been shown to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the detailed mechanisms in joints are still unclear, and their regulation remains to be solved. Here, we explored neutrophil extracellular trap (NET)osis in experimental models of arthritis and further investigated the effects of interleukin-6 (IL-6) inhibition in neutrophils and NETosis. In skins of peptide GPI-induced arthritis (pGIA), citrullinated protein was detected as well as citrullinated histone expression in immunized skin but this was not specific to pGIA. Citrullinated histone expression in pGIA joints was specific to pGIA and was merged with neutrophil elastase, suggesting NETosis. Neutrophils in joints tend to upregulate IL-6 receptors when compared with bone marrow neutrophils. Administration of mouse anti-IL-6 receptor antibodies in pGIA suppressed arthritis in association with a decrease in neutrophil infiltration and NETosis in joints. In the plasma of RA patients, citrullinated protein was significantly reduced after tocilizumab treatment. Our results suggest that IL-6 enhances neutrophil chemotaxis and NETosis in inflammatory joints and could be the source of citrullinated proteins. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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Review

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14 pages, 931 KiB

Open AccessReview

Mechanisms of Systemic Osteoporosis in Rheumatoid Arthritis

by Peter Pietschmann, Maria Butylina, Katharina Kerschan-Schindl and Wolfgang Sipos

Int. J. Mol. Sci. 2022, 23(15), 8740; https://doi.org/10.3390/ijms23158740 - 5 Aug 2022

Cited by 13 | Viewed by 3544

Abstract

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with [...] Read more.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with RA, was delineated. Autoimmune inflammatory processes, which lead to a systemic upregulation of inflammatory and osteoclastogenic cytokines, the production of autoantibodies, and Th cell senescence with a presumed disability to control the systemic immune system’s and osteoclastogenic status, may play important roles in the pathophysiology of osteoporosis in RA. Consequently, osteoclast activity increases, osteoblast function decreases and bone metabolic and mechanical properties deteriorate. Although a number of disease-modifying drugs to treat joint inflammation are available, data on the ability of these drugs to prevent fragility fractures are limited. Thus, specific treatment of osteoporosis should be considered in patients with RA and an associated increased risk of fragility fractures. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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14 pages, 1815 KiB

Open AccessReview

Inflammatory Arthritis and Bone Metabolism Regulated by Type 2 Innate and Adaptive Immunity

by Yasunori Omata, Michael Frech, Taku Saito, Georg Schett, Mario M. Zaiss and Sakae Tanaka

Int. J. Mol. Sci. 2022, 23(3), 1104; https://doi.org/10.3390/ijms23031104 - 20 Jan 2022

Cited by 5 | Viewed by 4778

Abstract

While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current [...] Read more.

While type 2 immunity has traditionally been associated with the control of parasitic infections and allergic reactions, increasing evidence suggests that type 2 immunity exerts regulatory functions on inflammatory diseases such as arthritis, and also on bone homeostasis. This review summarizes the current evidence of the regulatory role of type 2 immunity in arthritis and bone. Key type 2 cytokines, like interleukin (IL)-4 and IL-13, but also others such as IL-5, IL-9, IL-25, and IL-33, exert regulatory properties on arthritis, dampening inflammation and inducing resolution of joint swelling. Furthermore, these cytokines share anti-osteoclastogenic properties and thereby reduce bone resorption and protect bone. Cellular effectors of this action are both T cells (i.e., Th2 and Th9 cells), but also non-T cells, like type 2 innate lymphoid cells (ILC2). Key regulatory actions mediated by type 2 cytokines and immune cells on both inflammation as well as bone homeostasis are discussed. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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11 pages, 570 KiB

Open AccessReview

Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

by Frédéric Coutant

Int. J. Mol. Sci. 2021, 22(24), 13670; https://doi.org/10.3390/ijms222413670 - 20 Dec 2021

Cited by 15 | Viewed by 3920

Abstract

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In [...] Read more.

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In RA, the synovial fluid of patients is enriched by a subset of DC that derive from monocytes (Mo-DC), which promote deleterious Th17 responses. The characterization of environmental factors in the joint that impact on the development and the fate of human Mo-DC is therefore of great importance in RA. When monocytes leave the blood and infiltrate inflamed synovial tissues, the process of differentiation into Mo-DC can be influenced by interactions with soluble factors such as cytokines, local acidosis and dysregulated synoviocytes. Other molecular factors, such as the citrullination process, can also enhance osteoclast differentiation from Mo-DC, favoring bone damages in RA. Conversely, biotherapies used to control inflammation in RA, modulate also the process of monocyte differentiation into DC. The identification of the environmental mediators that control the differentiation of Mo-DC, as well as the underlying molecular signaling pathways, could constitute a major breakthrough for the development of new therapies in RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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11 pages, 277 KiB

Open AccessReview

Title Current Status of the Search for Biomarkers for Optimal Therapeutic Drug Selection for Patients with Rheumatoid Arthritis

by Haruka Tsuchiya and Keishi Fujio

Int. J. Mol. Sci. 2021, 22(17), 9534; https://doi.org/10.3390/ijms22179534 - 2 Sep 2021

Cited by 9 | Viewed by 2470

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive synovitis. It is significantly associated with disability, impaired quality of life, and premature mortality. Recently, the development of biological agents (including tumor necrosis factor-α and interleukin-6 receptor inhibitors) and Janus kinase inhibitors have [...] Read more.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by destructive synovitis. It is significantly associated with disability, impaired quality of life, and premature mortality. Recently, the development of biological agents (including tumor necrosis factor-α and interleukin-6 receptor inhibitors) and Janus kinase inhibitors have advanced the treatment of RA; however, it is still difficult to predict which drug will be effective for each patient. To break away from the current therapeutic approaches that could be described as a “lottery,” there is an urgent need to establish biomarkers that stratify patients in terms of expected therapeutic responsiveness. This review deals with recent progress from multi-faceted analyses of the synovial tissue in RA, which is now bringing new insights into diverse features at both the cellular and molecular levels and their potential links with particular clinical phenotypes. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

12 pages, 1113 KiB

Open AccessReview

Possible Roles of tRNA Fragments, as New Regulatory ncRNAs, in the Pathogenesis of Rheumatoid Arthritis

by Satoshi Yamasaki, Munetoshi Nakashima and Hiroaki Ida

Int. J. Mol. Sci. 2021, 22(17), 9481; https://doi.org/10.3390/ijms22179481 - 31 Aug 2021

Cited by 4 | Viewed by 2471

Abstract

Understanding the pathophysiology of rheumatoid arthritis (RA) has led to the successful development of molecule-targeted drugs for the treatment of RA. However, some RA patients are refractory to these treatments, suggesting that the pathological mechanism of the disease is not entirely understood. Genome [...] Read more.

Understanding the pathophysiology of rheumatoid arthritis (RA) has led to the successful development of molecule-targeted drugs for the treatment of RA. However, some RA patients are refractory to these treatments, suggesting that the pathological mechanism of the disease is not entirely understood. Genome and transcriptome analysis is essential for understanding the unknown pathophysiology of human diseases. Rapid and more comprehensive gene analysis technologies have revealed notable changes in the expression of coding RNA and non-coding RNA in RA patients. This review focuses on the current state of non-coding RNA research in relation to RA, especially on tRNA fragments. Interestingly, it has been found that tRNA fragments repress translation and are antiapoptotic. The association between tRNA fragments and various diseases has been studied, and this article reviews the possible role of tRNA fragments in RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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15 pages, 843 KiB

Open AccessReview

Cell-Free DNA in Rheumatoid Arthritis

by Teppei Hashimoto, Kohsuke Yoshida, Akira Hashiramoto and Kiyoshi Matsui

Int. J. Mol. Sci. 2021, 22(16), 8941; https://doi.org/10.3390/ijms22168941 - 19 Aug 2021

Cited by 28 | Viewed by 4563

Abstract

Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, [...] Read more.

Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis, and treatment of RA has highly varied outcomes. cfDNA in patients with RA is elevated in peripheral blood and synovial fluid and is associated with disease activity. Profiling of cfDNA in patients with RA may then be utilized in various aspects of clinical practice, such as the prediction of prognosis and treatment responses; monitoring disease state; and as a diagnostic marker. In this review, we discuss cfDNA in patients with RA, particularly the sources of cfDNA and the correlation of cfDNA with RA pathogenesis. We also highlight the potential of analyzing cfDNA profiles to guide individualized treatment approaches for RA. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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Other

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11 pages, 2075 KiB

Open AccessBrief Report

Methotrexate Alters the Expression of microRNA in Fibroblast-like Synovial Cells in Rheumatoid Arthritis

by Naoki Iwamoto, Kaori Furukawa, Yushiro Endo, Toshimasa Shimizu, Remi Sumiyoshi, Masataka Umeda, Tomohiro Koga, Shin-ya Kawashiri, Takashi Igawa, Kunihiro Ichinose, Mami Tamai, Tomoki Origuchi and Atsushi Kawakami

Int. J. Mol. Sci. 2021, 22(21), 11561; https://doi.org/10.3390/ijms222111561 - 26 Oct 2021

Cited by 9 | Viewed by 2039

Abstract

We aimed to investigate the effect of methotrexate (MTX) on microRNA modulation in rheumatoid arthritis fibroblast-like synovial cells (RA-FLS). RA-FLS were treated with MTX for 48 h. We then performed miRNA array analysis to investigate differentially expressed miRNAs. Transfection with miR-877-3p precursor and [...] Read more.

We aimed to investigate the effect of methotrexate (MTX) on microRNA modulation in rheumatoid arthritis fibroblast-like synovial cells (RA-FLS). RA-FLS were treated with MTX for 48 h. We then performed miRNA array analysis to investigate differentially expressed miRNAs. Transfection with miR-877-3p precursor and inhibitor were used to investigate the functional role of miR-877-3p in RA-FLS. Gene ontology analysis was used to investigate the cellular processes involving miR-877-3p. The production of cytokines/chemokines was screened by multiplex cytokine/chemokine bead assay and confirmed by ELISA and quantitative real-time PCR. The migratory and proliferative activities of RA-FLS were analyzed by wound healing assay and MKI-67 expression. MTX treatment altered the expression of 13 miRNAs (seven were upregulated and six were downregulated). Among them, quantitative real-time PCR confirmed that miR-877-3p was upregulated in response to MTX (1.79 ± 0.46-fold, p < 0.05). The possible target genes of miR-877-3p in RA-FLS revealed by the microarray analysis were correlated with biological processes. The overexpression of miR-877-3p decreased the production of GM-CSF and CCL3, and the overexpression of miR-877-3p inhibited migratory and proliferative activity. MTX altered the miR-877-3p expression on RA-FLS, and this alteration of miR-877-3p attenuated the abundant production of cytokines/chemokines and proliferative property of RA-FLS. Full article

(This article belongs to the Special Issue The Pathogenesis of Rheumatoid Arthritis—Breakthroughs in Molecular Mechanisms)

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