{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:25:03Z","timestamp":1790623503226,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T00:00:00Z","timestamp":1571097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["17H02136"],"award-info":[{"award-number":["17H02136"]}]},{"name":"JSPS KAKENHI","award":["18K10752"],"award-info":[{"award-number":["18K10752"]}]},{"name":"JSPS KAKENHI","award":["19K19914"],"award-info":[{"award-number":["19K19914"]}]},{"name":"Grant of Japan Sports Medicine Foundation","award":["2018"],"award-info":[{"award-number":["2018"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Exercise therapy inhibits joint destruction by suppressing pro-inflammatory cytokines. The efficacy of pharmacotherapy for rheumatoid arthritis differs depending on the phase of the disease, but that of exercise therapy for each phase is unknown. We assessed the differences in the efficacy of treadmill running on rheumatoid arthritis at various phases, using rat rheumatoid arthritis models. Rats with collagen-induced arthritis were used as rheumatoid arthritis models, and the phase after immunization was divided as pre-arthritis and established phases. Histologically, the groups with forced treadmill running in the established phase had significantly inhibited joint destruction compared with the other groups. The group with forced treadmill running in only the established phase had significantly better bone morphometry and reduced expression of connexin 43 and tumor necrosis factor \u03b1 in the synovial membranes compared with the no treadmill group. Furthermore, few cells were positive for cathepsin K immunostaining in the groups with forced treadmill running in the established phase. Our results suggest that the efficacy of exercise therapy may differ depending on rheumatoid arthritis disease activity. Active exercise during phases of decreased disease activity may effectively inhibit arthritis and joint destruction.<\/jats:p>","DOI":"10.3390\/ijms20205100","type":"journal-article","created":{"date-parts":[[2019,10,16]],"date-time":"2019-10-16T03:32:54Z","timestamp":1571196774000},"page":"5100","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Treadmill Running in Established Phase Arthritis Inhibits Joint Destruction in Rat Rheumatoid Arthritis Models"],"prefix":"10.3390","volume":"20","author":[{"given":"Yuta","family":"Fujii","sequence":"first","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroaki","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Arai","sequence":"additional","affiliation":[{"name":"Department of Sports and Para-Sports Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Shimomura","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuji","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Sports and Para-Sports Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsunao","family":"Kishida","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Tsuchida","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichiro","family":"Kamada","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Kaihara","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiharu","family":"Shirai","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryu","family":"Terauchi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8626-604X","authenticated-orcid":false,"given":"Shogo","family":"Toyama","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Ikoma","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osam","family":"Mazda","sequence":"additional","affiliation":[{"name":"Department of Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Mikami","sequence":"additional","affiliation":[{"name":"Department of Rehabilitation Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6590","DOI":"10.4049\/jimmunol.165.11.6590","article-title":"Stromal cell-derived factor-1-CXC chemokine receptor 4 interactions play a central role in CD4+ T cell accumulation in rheumatoid arthritis synovium","volume":"165","author":"Nanki","year":"2000","journal-title":"J. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1002\/art.27584","article-title":"Rheumatoid arthritis classification criteria: An American College of Rheumatology\/European League Against Rheumatism collaborative initiative","volume":"62","author":"Aletaha","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2205","DOI":"10.1056\/NEJMra1004965","article-title":"The pathogenesis of rheumatoid arthritis","volume":"365","author":"Mcknnes","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1016\/j.biopha.2017.05.055","article-title":"Rheumatoid arthritis: Recent advances on its etiology, role of cytokines and pharmacotherapy","volume":"92","author":"Alam","year":"2017","journal-title":"Biomed. Pharm."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/S0140-6736(99)05246-0","article-title":"Infliximab (chimeric anti-tumour necrosis factor \u03b1 monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial","volume":"354","author":"Maini","year":"1999","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1056\/NEJM200011303432202","article-title":"Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study group","volume":"343","author":"Lipsky","year":"2000","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1616","DOI":"10.1136\/annrheumdis-2013-205137","article-title":"Sirukumab. A human anti-interleukin-6 monoclonal antibody: A randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy","volume":"73","author":"Smolen","year":"2014","journal-title":"Ann. Rheum. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2968","DOI":"10.1002\/art.23940","article-title":"Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: The tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study","volume":"58","author":"Genovese","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Singh, J.A., Wells, G.A., Christensen, R., Tanjong Ghogomu, E., Maxwell, L., Macdonald, J.K., Filippini, G., Skoetz, N., Francis, D., and Lopes, L.C. (2011). Adverse effects of biologics: A network meta-analysis and Cochrane overview. Cochrane Database Syst. Rev., CD008794.","DOI":"10.1002\/14651858.CD008794"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/j.joca.2010.01.013","article-title":"OARSI recommendations for the management of hip and knee osteoarthritis, Part III: Changes in evidence following systematic cumulative update of research published through January 2009","volume":"18","author":"Zhang","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1016\/j.joca.2015.04.015","article-title":"Effects of short-term gentle treadmill walking on subchondral bone in a rat model of instability-induced osteoarthritis","volume":"23","author":"Iijima","year":"2015","journal-title":"Osteoarthr. Cartil."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s10741-007-9000-y","article-title":"Theoretical rationale and practical recommendations for cardiopulmonary exercise testing in patients with chronic heart failure","volume":"12","author":"Ingle","year":"2007","journal-title":"Heart Fail. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1016\/j.apmr.2018.03.014","article-title":"Effects of exercise training on pulmonary function in adults with chronic lung disease: A meta-analysis of randomized controlled trials","volume":"99","author":"Salcedo","year":"2018","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hurkmans, E., van der Giesen, F.J., Vliet Vlieland, T.P., Schoones, J., and Van den Ende, E.C. (2009). Dynamic exercise programs (aerobic capacity and\/or muscle strength training) in patients with rheumatoid arthritis. Vet. Res. Commun.","DOI":"10.1002\/14651858.CD006853.pub2"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1136\/ard.55.11.798","article-title":"Comparison of high and low intensity training in well controlled rheumatoid arthritis. Results of a randomised clinical trial","volume":"55","author":"Hazes","year":"1996","journal-title":"Ann. Rheum. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1093\/rheumatology\/ker330","article-title":"Efficacy of resistance exercises in rheumatoid arthritis: Meta-analysis of randomized controlled trials","volume":"51","author":"Baillet","year":"2012","journal-title":"Rheumatology."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shimomura, S., Inoue, H., Arai, Y., Nakagawa, S., Fujii, Y., Kishida, T., Ichimaru, S., Tsuchida, S., Shirai, T., and Ikoma, K. (2018). Treadmill running ameliorates destruction of articular cartilage and subchondral bone, not only synovitis, in a rheumatoid arthritis rat model. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061653"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"R237","DOI":"10.1186\/ar4080","article-title":"Comparative analysis of collagen type II-specific immune responses during development of collagen-induced arthritis in two B10 mouse strains","volume":"14","author":"Batsalova","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1136\/annrheumdis-2016-209830","article-title":"Possibilities for preventive treatment in rheumatoid arthritis? Lessons from experimental animal models of arthritis: A systematic literature review and meta-analysis","volume":"76","author":"Dekkers","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1136\/ard.62.8.783","article-title":"Local infusion of infliximab for the treatment of acute joint inflammation","volume":"62","author":"Bokarewa","year":"2003","journal-title":"Ann. Rheum. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1210\/er.2015-1114","article-title":"Cathepsin K inhibitors for osteoporosis: Biology, potential clinical utility, and lessons learned","volume":"38","author":"Drake","year":"2017","journal-title":"Endcr. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1074\/jbc.M805280200","article-title":"Cathepsin K activity-dependent regulation of osteoclast actin ring formation and bone resorption","volume":"284","author":"Wilson","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1002\/jor.22263","article-title":"Silencing the expression of connexin 43 decreases inflammation and joint destruction in experimental arthritis","volume":"31","author":"Tsuchida","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"55","DOI":"10.5606\/ArchRheumatol.2016.5597","article-title":"Expression of connexin 43 in synovial tissue of patients with rheumatoid arthritis","volume":"31","author":"Matsuki","year":"2016","journal-title":"Arch. Rheumatol."},{"key":"ref_25","first-page":"28321","article-title":"Mitogen-activated protein kinase (MAPK) activated by prostaglandin E2 phosphorylates connexin 43 and closes osteocytic hemichannels in response to continuous flow shear stress","volume":"47","author":"Manuel","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1002\/jor.22341","article-title":"Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice","volume":"31","author":"Bivi","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/art.38218","article-title":"Combination of tumor necrosis factor and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo","volume":"66","author":"Yokota","year":"2014","journal-title":"Arthritis Rheum."},{"key":"ref_28","first-page":"291","article-title":"Mechanical stress directly suppresses osteoclast differentiation in RAW264.7 cells","volume":"21","author":"Suzuki","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1084\/jem.20061775","article-title":"Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction","volume":"203","author":"Sato","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_30","first-page":"1945","article-title":"Collagen induced arthritis in rats. Contrasting effect of subcutaneous versus intradermal inoculation of type II collagen","volume":"25","author":"Bakharevski","year":"1998","journal-title":"J. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1613","DOI":"10.1002\/art.30311","article-title":"Transcriptome-wide gene regulation by gentle treadmill walking during the progression of monoiodoacetate-induced arthritis","volume":"63","author":"Nam","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Jin, H., Ma, N., Li, X., Kang, M., Guo, M., and Song, L. (2019). Application of GC\/MS-based metabonomic profiling in studying the therapeutic effects of Aconitum carmichaeli with Ampelopsis japonica extract on collagen-induced arthritis in rats. Molecules, 24.","DOI":"10.3390\/molecules24101934"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1002\/art.10850","article-title":"Placental immunomodulator ferritin, a novel immunoregulator, suppresses experimental arthritis","volume":"48","author":"Weinberger","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"211","DOI":"10.4103\/jomfp.JOMFP_234_16","article-title":"Validation of immunoexpression of tenascin-C in oral precancerous and cancerous tissues using ImageJ analysis with novel immunohistochemistry profiler plugin: An immunohistochemical quantitative analysis","volume":"21","author":"Mane","year":"2017","journal-title":"J. Oral Maxillofac. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Munemoto, M., Kido, A., Sakamoto, Y., Inoue, K., Yokoi, K., Shinohara, Y., and Tanaka, Y. (2016). Analysis of trabecular bone microstructure in osteoporotic femoral heads in human patients: In vivo study using multidetector row computed tomography. BMC Musculoskelet Disord., 17.","DOI":"10.1186\/s12891-015-0848-z"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/8756-3282(89)90140-3","article-title":"Star volume of marrow space and trabeculae of the first lumber vertebra: Sampling efficiency and biological variation","volume":"10","author":"Vesterby","year":"1989","journal-title":"Bone"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5100\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:26:21Z","timestamp":1760189181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/20\/5100"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,15]]},"references-count":36,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20205100"],"URL":"https:\/\/doi.org\/10.3390\/ijms20205100","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,15]]}}}