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      Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?

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          Abstract

          Fibroblast-like synoviocytes or synovial fibroblasts (FLS) are important cellular components of the inner layer of the joint capsule, referred to as the synovial membrane. They can be found in both layers of this synovial membrane and contribute to normal joint function by producing extracellular matrix components and lubricants. However, under inflammatory conditions like in rheumatoid arthritis (RA), they may start to proliferate, undergo phenotypical changes and become central elements in the perpetuation of inflammation through their direct and indirect destructive functions. Their importance in autoimmune joint disorders makes them attractive cellular targets, and as mesenchymal-derived cells, their inhibition may be carried out without immunosuppressive consequences. Here, we aim to give an overview of our current understanding of the target potential of these cells in RA.

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          Most cited references86

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          Toll-Like Receptor Signaling Pathways

          Toll-like receptors (TLRs) play crucial roles in the innate immune system by recognizing pathogen-associated molecular patterns derived from various microbes. TLRs signal through the recruitment of specific adaptor molecules, leading to activation of the transcription factors NF-κB and IRFs, which dictate the outcome of innate immune responses. During the past decade, the precise mechanisms underlying TLR signaling have been clarified by various approaches involving genetic, biochemical, structural, cell biological, and bioinformatics studies. TLR signaling appears to be divergent and to play important roles in many aspects of the innate immune responses to given pathogens. In this review, we describe recent progress in our understanding of TLR signaling regulation and its contributions to host defense.
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            Rheumatoid arthritis

            Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up. In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades. Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at the least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation. In this Primer, we discuss the epidemiology, pathophysiology, diagnosis and management of RA.
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              Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis.

              Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.
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                Author and article information

                Journal
                Ann Rheum Dis
                Ann Rheum Dis
                annrheumdis
                ard
                Annals of the Rheumatic Diseases
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0003-4967
                1468-2060
                August 2022
                17 June 2022
                : 81
                : 8
                : 1055-1064
                Affiliations
                [1 ] departmentDepartment of Physiology , Semmelweis University , Budapest, Hungary
                [2 ] Department of Rheumatology and Clinical Immunology, Semmelweis University , Budapest, Hungary
                [3 ] departmentDepartment of Internal Medicine and Oncology , Semmelweis University , Budapest, Hungary
                [4 ] Department of Genetics, Cell and Immunobiology, Semmelweis University , Budapest, Hungary
                [5 ] Heart and Vascular Center, Semmelweis University , Budapest, Hungary
                [6 ] departmentInstitute of Musculoskeletal Medicine , Medical Faculty of the Westphalian Wilhelm University , Münster, Germany
                Author notes
                [Correspondence to ] Dr Tamás Németh, Department of Physiology, Semmelweis University, Budapest, Hungary; nemeth.tamas@ 123456med.semmelweis-univ.hu
                Author information
                http://orcid.org/0000-0001-6854-4301
                http://orcid.org/0000-0003-1198-3228
                http://orcid.org/0000-0001-6514-0416
                Article
                annrheumdis-2021-222021
                10.1136/annrheumdis-2021-222021
                9279838
                35715191
                dac7505b-8631-4671-9203-32cba90ee196
                © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

                This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:  http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 17 December 2021
                : 22 May 2022
                Funding
                Funded by: Hungarian National Research, Development and Innovation Office;
                Award ID: FK 132251
                Funded by: Hungarian National Research, Development and Innovation Office;
                Award ID: K 131479
                Funded by: RTCure H2020;
                Award ID: 777357
                Categories
                Review
                1506
                2311
                Custom metadata
                unlocked

                Immunology
                fibroblasts,arthritis, rheumatoid,inflammation
                Immunology
                fibroblasts, arthritis, rheumatoid, inflammation

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