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      Small interfering RNAs in the management of human rheumatoid arthritis

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          Abstract

          Background

          Rheumatoid arthritis (RA) has unclear pathogenesis, but the molecules that feed its inflammatory state are known. Small interfering RNAs (siRNAs) are useful to identify molecular targets and evaluate the efficacy of specific drugs, and can themselves be used for therapeutic purposes.

          Sources of data

          A systematic search of different databases to March 2022 was performed to define the role of siRNAs in RA therapy. Twenty suitable studies were identified.

          Areas of agreement

          Small interfering RNAs can be useful in the study of inflammatory processes in RA, and identify possible therapeutic targets and drug therapies.

          Areas of controversy

          Many genes and cytokines participate in the inflammatory process of RA and can be regulated with siRNA. However, it is difficult to determine whether the responses to siRNAs and other drugs studied in human cells in vitro are similar to the responses in vivo.

          Growing points

          Inflammatory processes can be affected by the gene dysregulation of siRNAs on inflammatory cytokines.

          Areas timely for developing research

          To date, it is not possible to determine whether the pharmacological response of siRNAs on cells in vitro would be similar to what takes place in vivo for the diseases studied so far.

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          Most cited references55

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          Matrix metalloproteinases.

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            Matrix metalloproteinases: role in arthritis.

            The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury. In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix. The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage. In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction. Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints. Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints. To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.
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              Preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and publication bias.

              Publication bias is a major problem in evidence based medicine. As well as positive outcome studies being preferentially published or followed by full text publication authors are also more likely to publish positive results in English-language journals. This unequal distribution of trials leads to a selection bias in evidence l level studies, like systematic reviews, meta-analysis or health technology assessments followed by a systematic failure of interpretation and in clinical decisions. Publication bias in a systematic review occurs mostly during the selection process and a transparent selection process is necessary to avoid such bias. For systematic reviews/meta-analysis the PRISMA-statement (formerly known as QUOROM) is recommended, as it gives the reader for a better understanding of the selection process. In the future the use of trial registration for minimizing publication bias, mechanisms to allow easier access to the scientific literature and improvement in the peer review process are recommended to overcome publication bias. The use of checklists like PRISMA is likely to improve the reporting quality of a systematic review and provides substantial transparency in the selection process of papers in a systematic review. Copyright © 2010 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Br Med Bull
                Br Med Bull
                brimed
                British Medical Bulletin
                Oxford University Press
                0007-1420
                1471-8391
                March 2022
                29 April 2022
                29 April 2022
                : 142
                : 1
                : 34-43
                Affiliations
                Department of Trauma and Orthopaedic Surgery, AOU San Giovanni di Dio e Ruggi D’Aragona , Via San Leonardo 1, Salerno 84131, Italy
                Department of Medicine , Surgery and Dentistry, University of Salerno , Via S. Allende, Baronissi SA 84081, Italy
                Department of Trauma and Orthopaedic Surgery, AOU San Giovanni di Dio e Ruggi D’Aragona , Via San Leonardo 1, Salerno 84131, Italy
                Department of Medicine , Surgery and Dentistry, University of Salerno , Via S. Allende, Baronissi SA 84081, Italy
                Department of Trauma and Orthopaedic Surgery, AOU San Giovanni di Dio e Ruggi D’Aragona , Via San Leonardo 1, Salerno 84131, Italy
                Department of Medicine , Surgery and Dentistry, University of Salerno , Via S. Allende, Baronissi SA 84081, Italy
                Department of Trauma and Orthopaedic Surgery, AOU San Giovanni di Dio e Ruggi D’Aragona , Via San Leonardo 1, Salerno 84131, Italy
                Department of Medicine , Surgery and Dentistry, University of Salerno , Via S. Allende, Baronissi SA 84081, Italy
                Queen Mary University of London, Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Mile End Hospital , 275 Bancroft Road, London E1 4DG, UK
                School of Pharmacy and Bioengineering, Keele University School of Medicine , Thornburrow Drive, Stoke on Trent, ST4 7QB, UK
                Author notes
                Correspondence address. Department of Trauma and Orthopaedic Surgery, AOU San Giovanni di Dio e Ruggi D’Aragona, Via San Leonardo 1, Salerno 84131, Italy.E-mail: n.maffulli@ 123456qmul.ac.uk
                Article
                ldac012
                10.1093/bmb/ldac012
                9351475
                35488320
                70ebf86c-3a76-4702-8060-adf3e2633bf9
                © The Author(s) 2022. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 March 2022
                : 30 March 2022
                Page count
                Pages: 10
                Categories
                Invited Review
                AcademicSubjects/MED00010
                brimed/56

                Medicine
                rheumatoid arthritis,rheumatoid arthritis therapy,small interfering rna,short interfering rna,silencing rna,rna interference

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