20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Understanding the Molecular Mechanisms Underlying the Pathogenesis of Arthritis Pain Using Animal Models

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Arthritis, including osteoarthritis (OA) and rheumatoid arthritis (RA), is the leading cause of years lived with disability (YLD) worldwide. Although pain is the cardinal symptom of arthritis, which is directly related to function and quality of life, the elucidation of the mechanism underlying the pathogenesis of pain in arthritis has lagged behind other areas, such as inflammation control and regulation of autoimmunity. The lack of therapeutics for optimal pain management is partially responsible for the current epidemic of opioid and narcotic abuse. Recent advances in animal experimentation and molecular biology have led to significant progress in our understanding of arthritis pain. Despite the inherent problems in the extrapolation of data gained from animal pain studies to arthritis in human patients, the critical assessment of molecular mediators and translational studies would help to define the relevance of novel therapeutic targets for the treatment of arthritis pain. This review discusses biological and molecular mechanisms underlying the pathogenesis of arthritis pain determined in animal models of OA and RA, along with the methodologies used.

          Related collections

          Most cited references157

          • Record: found
          • Abstract: found
          • Article: found

          Aging, Cellular Senescence, and Cancer

          For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype.

            Cellular senescence suppresses cancer by forcing potentially oncogenic cells into a permanent cell cycle arrest. Senescent cells also secrete growth factors, proteases, and inflammatory cytokines, termed the senescence-associated secretory phenotype (SASP). Much is known about pathways that regulate the senescence growth arrest, but far less is known about pathways that regulate the SASP. We previously showed that DNA damage response (DDR) signalling is essential, but not sufficient, for the SASP, which is restrained by p53. Here, we delineate another crucial SASP regulatory pathway and its relationship to the DDR and p53. We show that diverse senescence-inducing stimuli activate the stress-inducible kinase p38MAPK in normal human fibroblasts. p38MAPK inhibition markedly reduced the secretion of most SASP factors, constitutive p38MAPK activation was sufficient to induce an SASP, and p53 restrained p38MAPK activation. Further, p38MAPK regulated the SASP independently of the canonical DDR. Mechanistically, p38MAPK induced the SASP largely by increasing NF-κB transcriptional activity. These findings assign p38MAPK a novel role in SASP regulation--one that is necessary, sufficient, and independent of previously described pathways.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group.

              Not all patients with rheumatoid arthritis can tolerate or respond to methotrexate, a standard treatment for this disease. There is evidence that antitumour necrosis factor alpha (TNFalpha) is efficacious in relief of signs and symptoms. We therefore investigated whether infliximab, a chimeric human-mouse anti-TNFalpha monoclonal antibody would provide additional clinical benefit to patients who had active rheumatoid arthritis despite receiving methotrexate. In an international double-blind placebo-controlled phase III clinical trial, 428 patients who had active rheumatoid arthritis, who had received continuous methotrexate for at least 3 months and at a stable dose for at least 4 weeks, were randomised to placebo (n=88) or one of four regimens of infliximab at weeks 0, 2, and 6. Additional infusions of the same dose were given every 4 or 8 weeks thereafter on a background of a stable dose of methotrexate (median 15 mg/week for > or =6 months, range 10-35 mg/wk). Patients were assessed every 4 weeks for 30 weeks. At 30 weeks, the American College of Rheumatology (20) response criteria, representing a 20% improvement from baseline, were achieved in 53, 50, 58, and 52% of patients receiving 3 mg/kg every 4 or 8 weeks or 10 mg/kg every 4 or 8 weeks, respectively, compared with 20% of patients receiving placebo plus methotrexate (p<0.001 for each of the four infliximab regimens vs placebo). A 50% improvement was achieved in 29, 27, 26, and 31% of infliximab plus methotrexate in the same treatment groups, compared with 5% of patients on placebo plus methotrexate (p<0.001). Infliximab was well-tolerated; withdrawals for adverse events as well as the occurrence of serious adverse events or serious infections did not exceed those in the placebo group. During 30 weeks, treatment with infliximab plus methotrexate was more efficacious than methotrexate alone in patients with active rheumatoid arthritis not previously responding to methotrexate.
                Bookmark

                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                14 January 2020
                January 2020
                : 21
                : 2
                : 533
                Affiliations
                [1 ]Division of Rheumatology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Gyeonggi 14068, Korea; jhi1126@ 123456naver.com (J.-I.H.); hoyo012@ 123456hanmail.net (I.Y.P.)
                [2 ]Institute for Skeletal Aging, Hallym University, Chuncheon 24252, Korea
                Author notes
                [* ]Correspondence: kimha@ 123456hallym.ac.kr ; Tel.: +82-31-380-1826
                [†]

                These authors contributed equally to this work.

                Article
                ijms-21-00533
                10.3390/ijms21020533
                7013391
                31947680
                3a0371a6-d0e8-416a-90b8-1ae37bff2d9c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 20 November 2019
                : 09 January 2020
                Categories
                Review

                Molecular biology
                osteoarthritis,rheumatoid arthritis,animal model,pain
                Molecular biology
                osteoarthritis, rheumatoid arthritis, animal model, pain

                Comments

                Comment on this article