{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T05:17:23Z","timestamp":1787807843414,"version":"build-2784847793"},"reference-count":31,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010612","name":"D\u00fczce \u00dcniversitesi","doi-asserted-by":"publisher","award":["2024.04.02.1512"],"award-info":[{"award-number":["2024.04.02.1512"]}],"id":[{"id":"10.13039\/501100010612","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024.04.02.1512"],"award-info":[{"award-number":["2024.04.02.1512"]}],"id":[{"id":"https:\/\/ror.org\/04175wc52","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Vascular endothelial growth factor (VEGF) has emerged as a potential therapeutic target in osteoarthritis (OA). Although several anti-VEGF agents are widely used in clinical practice, their comparative effects on osteoarthritic cartilage remain unclear. This study compared the histopathological effects of intra-articular bevacizumab, ranibizumab, and aflibercept in an experimental rat model of OA. Methods: Experimental OA was induced in 36 rats using anterior cruciate ligament transection. One month later, animals received two intra-articular injections of bevacizumab (2 mg\/kg), ranibizumab (0.5 mg\/kg), aflibercept (3.2 mg\/kg), or saline at 3-week intervals. Histopathological evaluation was performed using the Osteoarthritis Research Society International (OARSI) grading and staging system by two blinded pathologists. The primary outcome was the total OARSI score. Group comparisons were performed using the Kruskal\u2013Wallis test followed by Dunn\u2013Holm post hoc analysis. Results: Three animals were lost during anesthesia and surgical induction of OA before treatment allocation, leaving 33 rats for analysis. Significant overall differences were observed among the groups for the primary outcome of total OARSI score (p = 0.026) and the secondary outcomes of OARSI grade (p = 0.042) and OARSI stage (p = 0.019). Ranibizumab demonstrated numerically lower OARSI grade and total scores than the control group, whereas both groups had the same median OARSI stage score. Bevacizumab showed numerically lower OARSI grade and total scores than the control group but a slightly higher median stage score. Pairwise analysis showed significantly lower OARSI stage and total OARSI scores in the ranibizumab group than in the aflibercept group, whereas no significant differences were observed between any treatment group and the control group after correction for multiple comparisons. Conclusions: Anti-VEGF agents demonstrated differential histopathological responses in experimental OA. Although no treatment significantly improved histopathological outcomes compared with the control group after adjustment for multiple comparisons, ranibizumab showed lower OARSI stage and total scores than aflibercept. These findings indicate that the evaluated anti-VEGF agents may not exert equivalent biological effects and warrant further investigation in adequately powered experimental studies.<\/jats:p>","DOI":"10.3390\/jcm15176565","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T15:01:07Z","timestamp":1787670067000},"page":"6565","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative Histopathological Effects of Intra-Articular Bevacizumab, Ranibizumab, and Aflibercept in Experimental Osteoarthritis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5068-8024","authenticated-orcid":false,"given":"Ra\u015fit Emin","family":"Dalaslan","sequence":"first","affiliation":[{"name":"Orthopedics and Traumatology Department, Duzce University Medical Faculty, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-2339","authenticated-orcid":false,"given":"Mehmet","family":"Ar\u0131can","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Department, Duzce University Medical Faculty, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6719-3666","authenticated-orcid":false,"given":"Zekeriya Okan","family":"Karaduman","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Department, Duzce University Medical Faculty, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fccahid Osman","family":"Y\u00fccel","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Department, Duzce University Medical Faculty, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2651-8003","authenticated-orcid":false,"given":"S\u00f6nmez","family":"Sa\u011flam","sequence":"additional","affiliation":[{"name":"Orthopedics and Traumatology Department, Duzce University Medical Faculty, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8181-0739","authenticated-orcid":false,"given":"Fatih","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Duzce University, Duzce 81620, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00fccahit","family":"\u00c7elik","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics and Traumatology, Bal\u0131kesir Atat\u00fcrk City Hospital, Bal\u0131kesir 10100, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1016\/S0140-6736(19)30417-9","article-title":"Osteoarthritis","volume":"393","author":"Hunter","year":"2019","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.mcna.2019.10.007","article-title":"Osteoarthritis: Pathology, Diagnosis, and Treatment Options","volume":"104","author":"Abramoff","year":"2020","journal-title":"Med. Clin. N. Am."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Alad, M., Yousef, F., Epure, L.M., Lui, A., Grant, M.P., Merle, G., Eliopoulos, N., Barralet, J., Antoniou, J., and Mwale, F. (2025). Unraveling Osteoarthritis: Mechanistic Insights and Emerging Therapies Targeting Pain and Inflammation. Biomolecules, 15.","DOI":"10.3390\/biom15060874"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.joca.2024.10.008","article-title":"Osteoarthritis year in review 2024: Biology","volume":"33","author":"Zaucke","year":"2025","journal-title":"Osteoarthr. Cartil."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1080\/03008207.2025.2502591","article-title":"Mechanical insights into fat pads: A comparative study of infrapatellar and suprapatellar fat pads in osteoarthritis","volume":"66","author":"Pettenuzzo","year":"2025","journal-title":"Connect. Tissue Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1256","DOI":"10.1111\/hae.15097","article-title":"Pathogenesis of osteoarthritis, rheumatoid arthritis, and hemophilic arthropathy: The role of angiogenesis","volume":"30","author":"Caliogna","year":"2024","journal-title":"Haemophilia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/j.joca.2007.09.003","article-title":"The potential role of vascular endothelial growth factor (VEGF) in cartilage: How the angiogenic factor could be involved in the pathogenesis of osteoarthritis?","volume":"16","author":"Murata","year":"2008","journal-title":"Osteoarthr. Cartil."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1093\/rheumatology\/keh344","article-title":"Osteoarthritis, angiogenesis and inflammation","volume":"44","author":"Bonnet","year":"2005","journal-title":"Rheumatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.berh.2008.02.001","article-title":"Cartilage in normal and osteoarthritis conditions","volume":"22","author":"Boileau","year":"2008","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"13027","DOI":"10.1038\/s41598-017-13417-w","article-title":"Vascular Endothelial Growth Factor in Cartilage Development and Osteoarthritis","volume":"7","author":"Nagao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1007\/s10456-011-9249-6","article-title":"Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab","volume":"15","author":"Papadopoulos","year":"2012","journal-title":"Angiogenesis"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1136\/bjophthalmol-2011-300654","article-title":"Aflibercept (VEGF Trap-eye): The newest anti-VEGF drug","volume":"96","author":"Stewart","year":"2012","journal-title":"Br. J. Ophthalmol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1136\/bjophthalmol-2014-305252","article-title":"Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD","volume":"98","author":"Avery","year":"2014","journal-title":"Br. J. Ophthalmol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1186\/s13075-014-0427-y","article-title":"Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis","volume":"16","author":"Nagai","year":"2014","journal-title":"Arthritis Res. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13018-016-0346-5","article-title":"Animal models of osteoarthritis: Classification, update, and measurement of outcomes","volume":"11","author":"Kuyinu","year":"2016","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1302\/2046-3758.73.BJR-2017-0121.R2","article-title":"Comparison of pain behaviour and osteoarthritis progression between anterior cruciate ligament transection and osteochondral injury in rat models","volume":"7","author":"Tawonsawatruk","year":"2018","journal-title":"Bone Jt. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/s13018-026-06781-9","article-title":"Comparative effects of thiocolchicoside and etodolac on fracture healing in a rat femur model","volume":"21","author":"Bulum","year":"2026","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_18","first-page":"38","article-title":"Bevacizumab tested for treatment of knee osteoarthritis via inhibition of synovial vascular hyperplasia in rabbits","volume":"19","author":"Li","year":"2019","journal-title":"J. Orthop. Transl."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1351","DOI":"10.1016\/j.ophtha.2016.02.022","article-title":"Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial","volume":"123","author":"Wells","year":"2016","journal-title":"Ophthalmology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.joca.2005.07.014","article-title":"Osteoarthritis cartilage histopathology: Grading and staging","volume":"14","author":"Pritzker","year":"2006","journal-title":"Osteoarthr. Cartil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"S24","DOI":"10.1016\/j.joca.2010.05.030","article-title":"The OARSI histopathology initiative\u2014Recommendations for histological assessments of osteoarthritis in the rat","volume":"18","author":"Gerwin","year":"2010","journal-title":"Osteoarthr. Cartil."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Vadal\u00e0, G., Ambrosio, L., Cattani, C., Bernardini, R., Giacalone, A., Papalia, R., and Denaro, V. (2021). Bevacizumab Arrests Osteoarthritis Progression in a Rabbit Model: A Dose-Escalation Study. J. Clin. Med., 10.","DOI":"10.3390\/jcm10132825"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/s00296-026-06250-w","article-title":"Intra-articular VEGF inhibition attenuates cartilage degeneration in a rat model of post-traumatic osteoarthritis: A pilot histopathological study","volume":"46","author":"Bayram","year":"2026","journal-title":"Rheumatol. Int."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s13018-023-03512-2","article-title":"Bevacizumab suppressed degenerative changes in articular cartilage explants from patients with osteoarthritis of the knee","volume":"18","author":"Sotozawa","year":"2023","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1002\/jbmr.2828","article-title":"Targeting VEGF and Its Receptors for the Treatment of Osteoarthritis and Associated Pain","volume":"31","author":"Hamilton","year":"2016","journal-title":"J. Bone Miner. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00005-014-0285-y","article-title":"Distinct VEGF functions during bone development and homeostasis","volume":"62","author":"Liu","year":"2014","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/S0002-9440(10)63808-4","article-title":"Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage","volume":"162","author":"Enomoto","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"675","DOI":"10.7150\/ijbs.79125","article-title":"Targeting Vascular Endothelial Growth Factor Receptors as a Therapeutic Strategy for Osteoarthritis and Associated Pain","volume":"19","author":"Ma","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"112","DOI":"10.4103\/0974-620X.142591","article-title":"Vascular endothelial growth factor trap-eye and trap technology: Aflibercept from bench to bedside","volume":"7","year":"2014","journal-title":"Oman J. Ophthalmol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Le, T.H.V., and Kwon, S.-M. (2021). Vascular Endothelial Growth Factor Biology and Its Potential as a Therapeutic Target in Rheumatic Diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105387"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1007\/s11912-013-0368-7","article-title":"Aflibercept\u2014A Decoy VEGF Receptor","volume":"16","author":"Ciombor","year":"2014","journal-title":"Curr. Oncol. Rep."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/17\/6565\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T04:19:10Z","timestamp":1787804350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/17\/6565"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":31,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["jcm15176565"],"URL":"https:\/\/doi.org\/10.3390\/jcm15176565","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}