{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T22:45:27Z","timestamp":1784069127913,"version":"3.55.0"},"reference-count":31,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T00:00:00Z","timestamp":1691625600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["19K11347"],"award-info":[{"award-number":["19K11347"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22H03455"],"award-info":[{"award-number":["22H03455"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>We investigated the effect of regular walking exercise prior to knee osteoarthritis (OA) on pain and synovitis in a rat monoiodoacetic acid (MIA)-induced knee OA model. Seventy-one male Wistar rats were divided into three groups: (<jats:italic>i<\/jats:italic>) Sedentary + OA, (<jats:italic>ii<\/jats:italic>) Exercise + OA, and (<jats:italic>iii<\/jats:italic>) Sedentary + Sham groups. The Exercise + OA group underwent a regular treadmill walking exercise at 10 m\/min (60 min\/day, 5 days\/week) for 6 weeks, followed by a 2-mg MIA injection in the right knee. The right knee joint was removed from rats in this group at the end of the 6-week exercise period and at 1 and 6 weeks after the MIA injection. After the 6 weeks of treadmill exercise but before MIA injection, there were no significant differences among the three groups in the pressure pain threshold, whereas at 1 week post-injection, the Exercise + OA group\u2019s pressure pain threshold was significantly higher than that in the Sedentary + OA group, and this difference persisted until the end of the experimental period. The histological changes in articular cartilage and subchondral bone revealed by toluidine blue staining showed no difference between the Sedentary + OA and EX + OA groups. The expression levels of interleukin (IL)-4 and IL-10 mRNA in the infrapatellar fat pad and synovium were significantly increased by the treadmill exercise. Significant reductions in the number of CD68-, CD11c-positive cells and IL-1\u03b2 mRNA expression and an increase in the number of CD206-positive cells were observed at 1 week after the MIA injection in the Exercise + OA group compared to the Sedentary + OA group. These results suggest that regular walking exercise prior to the development of OA could alleviate joint pain through increases in the expressions of anti-inflammatory cytokines in the rat infrapatellar fat pad and synovium.<\/jats:p>","DOI":"10.1371\/journal.pone.0289765","type":"journal-article","created":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T17:42:08Z","timestamp":1691689328000},"page":"e0289765","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Regular walking exercise prior to knee osteoarthritis reduces joint pain in an animal model"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5621-2756","authenticated-orcid":true,"given":"Junya","family":"Sakamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syouta","family":"Miyahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoko","family":"Motokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumi","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Sasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Honda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Okita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,8,10]]},"reference":[{"key":"pone.0289765.ref001","doi-asserted-by":"crossref","first-page":"e0178621","DOI":"10.1371\/journal.pone.0178621","article-title":"Effective treatment options for musculoskeletal pain in primary care: A systematic overview of current evidence","volume":"12","author":"OO Babatunde","year":"2017","journal-title":"PLOS ONE"},{"key":"pone.0289765.ref002","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1093\/aje\/kwr087","article-title":"Physical exercise, body mass index, and risk of chronic pain in the low back and neck\/shoulders: Longitudinal data from the Nord-Trondelag Health Study","volume":"174","author":"TI Nilsen","year":"2011","journal-title":"Am J Epidemiol"},{"key":"pone.0289765.ref003","doi-asserted-by":"crossref","first-page":"863","DOI":"10.2478\/s13382-014-0315-3","article-title":"Relationship between daily physical activity level and low back pain in young, female desk-job workers","volume":"27","author":"G. Kayihan","year":"2014","journal-title":"Int J Occup Med Environ Health"},{"key":"pone.0289765.ref004","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1016\/j.pain.2011.04.029","article-title":"Associations between recreational exercise and chronic pain in the general population: Evidence from the HUNT 3 study","volume":"152","author":"T Landmark","year":"2011","journal-title":"Pain"},{"key":"pone.0289765.ref005","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1152\/japplphysiol.01317.2012","article-title":"Regular physical activity prevents development of chronic pain and activation of central neurons","volume":"114","author":"KA Sluka\u2019","year":"2013","journal-title":"J Appl Physiol"},{"key":"pone.0289765.ref006","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1097\/j.pain.0000000000000607","article-title":"Prior voluntary wheel running attenuates neuropathic pain","volume":"157","author":"PM Grace","year":"2016","journal-title":"Pain"},{"key":"pone.0289765.ref007","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1097\/j.pain.0000000000001109","article-title":"Interleukin-4 mediates the analgesia produced by low-intensity exercise in mice with neuropathic pain","volume":"159","author":"F Bobinski","year":"2018","journal-title":"Pain"},{"key":"pone.0289765.ref008","doi-asserted-by":"crossref","first-page":"5620","DOI":"10.1007\/s12035-016-0095-9","article-title":"High-intensity swimming exercise decreases glutamate-induced nociception by activation of G-protein-coupled receptors inhibiting phosphorylated protein kinase A","volume":"54","author":"DF Martins","year":"2017","journal-title":"Mol Neurobiol"},{"key":"pone.0289765.ref009","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neuroscience.2019.12.017","article-title":"Swimming physical training prevented the onset of acute muscle pain by a mechanism dependent of PPAR\u03b3 receptors and CINC-1","volume":"427","author":"G de Azambuja","year":"2020","journal-title":"Neuroscience"},{"key":"pone.0289765.ref010","doi-asserted-by":"crossref","first-page":"511","DOI":"10.3390\/ijms20030511","article-title":"Moderate physical activity as a prevention method for knee osteoarthritis and the role of synoviocytes as biological key","volume":"20","author":"P Castrogiovanni","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0289765.ref011","doi-asserted-by":"crossref","first-page":"111","DOI":"10.3389\/fimmu.2020.00111","article-title":"Macrophage: A potential target on cartilage regeneration","volume":"11","author":"TL Fernandes","year":"2020","journal-title":"Front Immunol"},{"key":"pone.0289765.ref012","doi-asserted-by":"crossref","first-page":"32407","DOI":"10.18632\/oncotarget.16299","article-title":"IL-33\/ST2-mediated inflammation in macrophages is directly abrogated by IL-10 during rheumatoid arthritis","volume":"8","author":"S Chen","year":"2017","journal-title":"Oncotarget"},{"key":"pone.0289765.ref013","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1136\/annrheumdis-2013-203355","article-title":"Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: Influences of age, gender and osteoarthritis affecting other joints","volume":"73","author":"D Prieto-Alhambra","year":"2014","journal-title":"Ann Rheum Dis"},{"key":"pone.0289765.ref014","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/art.1780270212","article-title":"Experimental arthritis induced by intraarticular injection of allogenic cartilaginous particles into rabbit knees","volume":"27","author":"CH Evans","year":"1984","journal-title":"Arthritis Rheum"},{"key":"pone.0289765.ref015","doi-asserted-by":"crossref","first-page":"1599","DOI":"10.1136\/ard.2006.067470","article-title":"Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis","volume":"66","author":"CL Hill","year":"2007","journal-title":"Ann Rheum Dis"},{"key":"pone.0289765.ref016","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1136\/ard.2009.121426","article-title":"Relation of synovitis to knee pain using contrast-enhanced MRIs","volume":"69","author":"K Baker","year":"2010","journal-title":"Ann Rheum Dis"},{"key":"pone.0289765.ref017","first-page":"1278","article-title":"Maximum oxygen consumption of rats and its changes with various experimental procedures","volume":"47","author":"TG Bedford","year":"1979","journal-title":"J Appl Physiol Respir Environ Exerc Physiol"},{"key":"pone.0289765.ref018","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1161\/hc3901.095960","article-title":"Exercise standards for testing and training: A statement for healthcare professionals from the American Heart Association","volume":"104","author":"GF Fletcher","year":"2001","journal-title":"Circulation"},{"key":"pone.0289765.ref019","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.pain.2004.08.004","article-title":"Pain related behaviour in two models of osteoarthritis in the rat knee","volume":"112","author":"J Fernihough","year":"2004","journal-title":"Pain"},{"issue":"Suppl 3","key":"pone.0289765.ref020","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.joca.2010.05.030","article-title":"The OARSI histopathology initiative\u2013Recommendations for histological assessments of osteoarthritis in the rat","author":"N Gerwin","year":"2010","journal-title":"Osteoarthritis Cartilage"},{"key":"pone.0289765.ref021","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1172\/JCI121561","article-title":"Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain","volume":"129","author":"S Zhu","year":"2019","journal-title":"J Clin Invest"},{"key":"pone.0289765.ref022","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13075-016-0983-4","article-title":"From osteoarthritic synovium to synovial-derived cells characterization: Synovial macrophages are key effector cells","volume":"18","author":"C Manferdini","year":"2016","journal-title":"Arthritis Res Ther"},{"key":"pone.0289765.ref023","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1002\/art.24505","article-title":"The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases","volume":"60","author":"JA Hamilton","year":"2009","journal-title":"Arthritis Rheum"},{"key":"pone.0289765.ref024","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1111\/joa.12662","article-title":"Evidence for plical support of the patella","volume":"231","author":"RM Geraghty","year":"2017","journal-title":"J Anat"},{"key":"pone.0289765.ref025","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1136\/annrheumdis-2016-210478","article-title":"Knee and hip intra-articular adipose tissues (IAATs) compared with autologous subcutaneous adipose tissue: a specific phenotype for a central player in osteoarthritis","volume":"76","author":"F Eymard","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"pone.0289765.ref026","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nri978","article-title":"Alternative activation of macrophages","volume":"3","author":"S. Gordon","year":"2003","journal-title":"Nat Rev Immunol"},{"key":"pone.0289765.ref027","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1084\/jem.174.5.1209","article-title":"Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes","volume":"174","author":"R de Waal Malefyt","year":"1991","journal-title":"J Exp Med"},{"key":"pone.0289765.ref028","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11926-021-00997-w","article-title":"Involvement of macrophages and spinal microglia in osteoarthritis pain","volume":"23","author":"TT Pan","year":"2021","journal-title":"Curr Rheumatol Rep"},{"key":"pone.0289765.ref029","doi-asserted-by":"crossref","first-page":"e0219902","DOI":"10.1371\/journal.pone.0219902","article-title":"Eight-year trajectories of changes in health-related quality of life in knee osteoarthritis: Data from the Osteoarthritis Initiative (OAI)","volume":"14","author":"S T\u00f6rm\u00e4lehto","year":"2019","journal-title":"PLOS ONE"},{"key":"pone.0289765.ref030","first-page":"e0219902","article-title":"Cost analysis of chronic pain due to musculoskeletal disorders in Chile","volume":"14","author":"MA Espinoza","year":"2019","journal-title":"PLOS ONE"},{"key":"pone.0289765.ref031","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s13075-017-1229-9","article-title":"Synovitis in osteoarthritis: current understanding with therapeutic implications","volume":"19","author":"A Mathiessen","year":"2017","journal-title":"Arthritis Res Ther"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289765","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T17:42:32Z","timestamp":1691689352000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0289765"}},"subtitle":[],"editor":[{"given":"Tanja","family":"Grubi\u0107 Kezele","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2023,8,10]]},"references-count":31,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,8,10]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0289765","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,10]]}}}