{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:11:23Z","timestamp":1760145083958,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T00:00:00Z","timestamp":1718236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP16K10919"],"award-info":[{"award-number":["JP16K10919"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Angiogenesis and vascular endothelial growth factor (VEGF) are involved in osteoarthritis (OA). We previously reported the inhibitory effect of bevacizumab in a rabbit model of OA. In the current study, we investigated the effects of lenvatinib, an angiogenesis inhibitor targeting the VEGF and fibroblast growth factor receptors, on synovitis, osteophyte formation, and cartilage degeneration in a rabbit OA model. Posttraumatic OA was induced by anterior cruciate ligament transection (ACLT) on one knee of each rabbit. Rabbits were placed into four groups according to the following lenvatinib doses: untreated control (n = 12), L0.3: 0.3 mg\/kg\/day (n = 15), L1.0: 1.0 mg\/kg\/day (n = 14), and L3.0: 3.0 mg\/kg\/day (n = 13) groups. We evaluated limb pain using the weight distribution ratio measured with an incapacitance tester, macroscopic osteophyte formation, and femoral condyle synovium and cartilage histology. For cartilage evaluation, the following distal sites of the femur were evaluated separately: femoral\u2013tibial (FT), femoral\u2013patellar (FP), and femoral corner (between FP and FT). The weight distribution ratio at 12 weeks after surgery was higher in the L0.3 and L1.0 groups than in the control group. Osteophyte formation and synovitis scores were significantly lower in the L0.3, L1.0, and L3.0 groups than in the control group. The Osteoarthritis Research Society International scores of the FT, corner, and FP sites in the L0.3 group were lower than in the control group. The cartilage thickness ratio at the FT and corner sites was significantly lower in the L0.3 group than in the control group. Krenn\u2019s grading system of cartilage synovitis showed that all lenvatinib-administered groups had significantly lower scores than the control group. MMP3 expression level in cartilage tissue was significantly lower in the L3.0 group compared with the other three groups. ADAMTS5 expression was lower in the L3.0 group compared with the control and L0.3 groups. Oral administration of lenvatinib inhibited synovitis, osteophyte formation, and cartilage degeneration and reduced pain in a rabbit ACLT model. Lenvatinib is an oral VEGF inhibitor that is easier to administer than other VEGF inhibitors and may have potential as a treatment of posttraumatic OA.<\/jats:p>","DOI":"10.3390\/ijms25126514","type":"journal-article","created":{"date-parts":[[2024,6,14]],"date-time":"2024-06-14T03:52:53Z","timestamp":1718337173000},"page":"6514","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Disease-Modifying Effects of Lenvatinib, a Multiple Receptor Tyrosine Kinase Inhibitor, on Posttraumatic Osteoarthritis of the Knee"],"prefix":"10.3390","volume":"25","author":[{"given":"Yasuyuki","family":"Sogo","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8789-2501","authenticated-orcid":false,"given":"Eriko","family":"Toyoda","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiro","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Tokai University Hachioji Hospital, 1838 Ishikawa-cho, Hachioji 192-0032, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0217-1324","authenticated-orcid":false,"given":"Takumi","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daichi","family":"Takizawa","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9038-0446","authenticated-orcid":false,"given":"Masahiko","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4049-7325","authenticated-orcid":false,"given":"Masato","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"},{"name":"Center for Musculoskeletal innovative Research and Advancement (C-MiRA), Graduate School of Medicine, Tokai University, 143 Shimokasuya, Isehara 259-1193, Kanagawa, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1002\/1529-0131(199805)41:5<778::AID-ART4>3.0.CO;2-V","article-title":"Estimates of the Prevalence of Arthritis and Selected Musculoskeletal Disorders in the United States","volume":"41","author":"Lawrence","year":"1998","journal-title":"Arthritis Rheum."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1007\/s11420-011-9248-6","article-title":"Osteoarthritis as a whole joint disease","volume":"8","author":"Poole","year":"2012","journal-title":"HSS J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/nrrheum.2010.191","article-title":"Genetic epidemiology of hip and knee osteoarthritis","volume":"7","author":"Valdes","year":"2011","journal-title":"Nat. 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