{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T17:04:13Z","timestamp":1770224653912,"version":"3.49.0"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007041","name":"University of Zaragoza","doi-asserted-by":"crossref","award":["2022\/0396"],"award-info":[{"award-number":["2022\/0396"]}],"id":[{"id":"10.13039\/501100007041","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100010067","name":"Gobierno de Arag\u00f3n","doi-asserted-by":"publisher","award":["B31_20R"],"award-info":[{"award-number":["B31_20R"]}],"id":[{"id":"10.13039\/501100010067","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010067","name":"Gobierno de Arag\u00f3n","doi-asserted-by":"publisher","award":["B31_23R"],"award-info":[{"award-number":["B31_23R"]}],"id":[{"id":"10.13039\/501100010067","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Exobiopharma, S.L."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Background\/Objectives: Knee osteoarthritis stands as the highest prevalent joint disease worldwide, affecting millions of adults and significantly impairing mobility and quality of life. Pro-inflammatory cells and cytokines are considered key players in the pathophysiology of the disease. In previous work, two anti-inflammatory therapeutic approaches were developed: a secretome enriched in anti-inflammatory cytokines, and nanoliposome-bound TRAIL (LUV-TRAIL), with proven efficacy against rheumatoid arthritis in rabbits. Methods: In this work, we evaluated the ability of these treatments to prevent the development of osteoarthritis (OA) in an ovine model following meniscectomies. Two weeks after the surgeries, knees were treated with several rounds of single or combined therapy, and then sheep were left untreated for several months. Knee damage was followed by X-ray analysis and, after sacrifice, assessed through macroscopic inspection, histological determinations, and inflammatory cytokine measurements. Results: The combined therapy had a significant positive effect against osteoarthritis development. Specifically, the combination is capable of improving knee injury in the first stages of OA in several parameters, such as synovial hyperplasia and tibial plateau damage, which are two of the most frequently damaged areas. Other markers, such as synovial inflammation and X-ray and macroscopic images, also presented a tendency to improved scores. Conclusions: The combination of the secretome with LUV-TRAIL represents a promising therapy worth exploring further in osteoarthritis treatment and\/or prevention.<\/jats:p>","DOI":"10.3390\/pharmaceutics18020193","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:48:08Z","timestamp":1770025688000},"page":"193","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Combination of Immunomodulatory Secretome and Liposome-Bound TRAIL Improves Knee Osteoarthritis Symptoms in an Ovine Model"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1710-4821","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Marco-Brualla","sequence":"first","affiliation":[{"name":"Biochemistry and Molecular and Cell Biology Department, Arag\u00f3n Health Research Institute (IIS-Arag\u00f3n), University of Zaragoza, 50009 Zaragoza, Spain"},{"name":"Facultad de Farmacia, Universidad San Pablo-CEU, 28660 Boadilla del Monte, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2587-7506","authenticated-orcid":false,"given":"Fel\u00edcito","family":"Garc\u00eda-\u00c1lvarez","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6409-6000","authenticated-orcid":false,"given":"Sara","family":"Fuente","sequence":"additional","affiliation":[{"name":"The Agri-Food Institute of Arag\u00f3n (IA2), Veterinary Teaching Hospital, University of Zaragoza, 50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pablo","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Ready for Trading (R4T), Living Cells Molecular and Cell Biology Research Laboratories, Fuenlabrada University Hospital, 28942 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1286-4968","authenticated-orcid":false,"given":"Arantza","family":"Vitoria","sequence":"additional","affiliation":[{"name":"The Agri-Food Institute of Arag\u00f3n (IA2), Veterinary Teaching Hospital, University of Zaragoza, 50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8712-2275","authenticated-orcid":false,"given":"Francisco Jos\u00e9","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"The Agri-Food Institute of Arag\u00f3n (IA2), Veterinary Teaching Hospital, University of Zaragoza, 50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3054-4589","authenticated-orcid":false,"given":"Juan Pedro","family":"Lapuente-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Ready for Trading (R4T), Living Cells Molecular and Cell Biology Research Laboratories, Fuenlabrada University Hospital, 28942 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3043-147X","authenticated-orcid":false,"given":"Luis","family":"Mart\u00ednez-Lostao","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7188-0461","authenticated-orcid":false,"given":"Antonio","family":"Romero","sequence":"additional","affiliation":[{"name":"The Agri-Food Institute of Arag\u00f3n (IA2), Veterinary Teaching Hospital, University of Zaragoza, 50013 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5175-8394","authenticated-orcid":false,"given":"Alberto","family":"Anel","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular and Cell Biology Department, Arag\u00f3n Health Research Institute (IIS-Arag\u00f3n), University of Zaragoza, 50009 Zaragoza, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/S0140-6736(24)02322-5","article-title":"Osteoarthritis","volume":"405","author":"Kloppenburg","year":"2025","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e508","DOI":"10.1016\/S2665-9913(23)00163-7","article-title":"Global, regional, and national burden of osteoarthritis, 1990\u20132020 and projections to 2050: A systematic analysis for the Global Burden of Disease Study 2021","volume":"5","author":"Steinmetz","year":"2023","journal-title":"Lancet Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Giorgino, R., Albano, D., Fusco, S., Peretti, G.M., Mangiavini, L., and Messina, C. 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