{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:48:19Z","timestamp":1787028499175,"version":"build-2736575974"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,4]],"date-time":"2023-02-04T00:00:00Z","timestamp":1675468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Bologna","award":["ex-RFO"],"award-info":[{"award-number":["ex-RFO"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoarthritis (OA) is described as a chronic degenerative disease characterized by the loss of articular cartilage. Senescence is a natural cellular response to stressors. Beneficial in certain conditions, the accumulation of senescent cells has been implicated in the pathophysiology of many diseases associated with aging. Recently, it has been demonstrated that mesenchymal stem\/stromal cells isolated from OA patients contain many senescent cells that inhibit cartilage regeneration. However, the link between cellular senescence in MSCs and OA progression is still debated. In this study, we aim to characterize and compare synovial fluid MSCs (sf-MSCs), isolated from OA joints, with healthy sf-MSCs, investigating the senescence hallmarks and how this state could affect cartilage repair. Sf-MSCs were isolated from tibiotarsal joints of healthy and diseased horses with an established diagnosis of OA with an age ranging from 8 to 14 years. Cells were cultured in vitro and characterized for cell proliferation assay, cell cycle analysis, ROS detection assay, ultrastructure analysis, and the expression of senescent markers. To evaluate the influence of senescence on chondrogenic differentiation, OA sf-MSCs were stimulated in vitro for up to 21 days with chondrogenic factors, and the expression of chondrogenic markers was compared with healthy sf-MSCs. Our findings demonstrated the presence of senescent sf-MSCs in OA joints with impaired chondrogenic differentiation abilities, which could have a potential influence on OA progression.<\/jats:p>","DOI":"10.3390\/ijms24043109","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:34:30Z","timestamp":1675654470000},"page":"3109","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Implication of Cellular Senescence in Osteoarthritis: A Study on Equine Synovial Fluid Mesenchymal Stromal Cells"],"prefix":"10.3390","volume":"24","author":[{"given":"Gabriella","family":"Teti","sequence":"first","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University di Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Mazzotti","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Vetmedica GmbH, 55218 Ingelheim am Rhein, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7935-284X","authenticated-orcid":false,"given":"Valentina","family":"Gatta","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University di Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Chiarini","sequence":"additional","affiliation":[{"name":"Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Laura","family":"Alfieri","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences, University di Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirella","family":"Falconi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/nm.3651","article-title":"Stem cell aging: Mechanisms, regulators and therapeutic opportunities","volume":"20","author":"Oh","year":"2014","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","article-title":"The hallmarks of aging","volume":"153","author":"Blasco","year":"2013","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Mazzotti, E., Teti, G., Falconi, M., Chiarini, F., Barboni, B., Mazzotti, A., and Muttini, A. (2019). Age-Related Alterations Affecting the Chondrogenic Differentiation of Synovial Fluid Mesenchymal Stromal Cells in an Equine Model. Cells, 8.","DOI":"10.3390\/cells8101116"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.trsl.2020.06.007","article-title":"Cellular senescence in age-related disorders","volume":"226","author":"Kaur","year":"2020","journal-title":"Transl. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"111515","DOI":"10.1016\/j.mad.2021.111515","article-title":"Cellular senescence in vascular wall mesenchymal stromal cells, a possible contribution to the development of aortic aneurysm","volume":"197","author":"Teti","year":"2021","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"866718","DOI":"10.3389\/fragi.2022.866718","article-title":"Cellular Senescence and Ageing: Mechanisms and Interventions","volume":"3","author":"Mylonas","year":"2022","journal-title":"Front. Aging"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.tcb.2018.02.001","article-title":"Hallmarks of Cellular Senescence","volume":"28","author":"Nehme","year":"2018","journal-title":"Trends Cell Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.cell.2019.10.005","article-title":"Cellular Senescence: Defining a Path Forward","volume":"179","author":"Gorgoulis","year":"2019","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"645593","DOI":"10.3389\/fcell.2021.645593","article-title":"Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype","volume":"9","author":"Kumari","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/bs.acc.2020.04.002","article-title":"Pathophysiological landscape of osteoarthritis","volume":"100","author":"Kulkarni","year":"2021","journal-title":"Adv. Clin. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1038\/s41584-022-00749-9","article-title":"Synovial inflammation in osteoarthritis progression","volume":"18","author":"Coras","year":"2022","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1172\/JCI95147","article-title":"Senescent cells and osteoarthritis: A painful connection","volume":"128","author":"Jeon","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1002\/art.21212","article-title":"Comparison of human stem cells derived from various mesenchymal tissues: Superiority of synovium as a cell source","volume":"52","author":"Sakaguchi","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1007\/s11999-013-3418-4","article-title":"Mesenchymal stem cells in synovial fluid increase after meniscus injury","volume":"472","author":"Matsukura","year":"2014","journal-title":"Clin. Orthop. Relat. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1093\/rheumatology\/ken114","article-title":"Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans","volume":"47","author":"Morito","year":"2008","journal-title":"Rheumatology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e24353","DOI":"10.1002\/jcla.24353","article-title":"Human adipose and synovial mesenchymal stem cells improve osteoarthritis in rats by reducing chondrocyte reactive oxygen species and inhibiting inflammatory response","volume":"36","author":"Liu","year":"2022","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1186\/s13287-018-1071-2","article-title":"In vitro and in vivo potentialities for cartilage repair from human advanced knee osteoarthritis synovial fluid-derived mesenchymal stem cells","volume":"9","author":"Neybecker","year":"2018","journal-title":"Stem Cell Res. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9128","DOI":"10.18632\/aging.102379","article-title":"Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development","volume":"11","author":"Malaise","year":"2019","journal-title":"Aging"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41584-020-00533-7","article-title":"Mechanisms and therapeutic implications of cellular senescence in osteoarthritis","volume":"17","author":"Coryell","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.bbrc.2007.08.033","article-title":"Pluripotent marker expression and differentiation of human second trimester Mesenchymal Stem Cells","volume":"362","author":"Gonzalez","year":"2007","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1080\/14653240600855905","article-title":"Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement","volume":"8","author":"Dominici","year":"2006","journal-title":"Cytotherapy"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"S386","DOI":"10.21037\/atm.2019.12.128","article-title":"Taking in consideration the bystander effects of articular senescence","volume":"7","author":"Brondello","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"102213","DOI":"10.1016\/j.coph.2022.102213","article-title":"Targeting cellular senescence as a novel treatment for osteoarthritis","volume":"64","author":"Coryell","year":"2022","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_24","first-page":"e32280","article-title":"Adult Stem Cells for Cartilage Regeneration","volume":"14","author":"Ismail","year":"2022","journal-title":"Cureus"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"151713","DOI":"10.1016\/j.acthis.2021.151713","article-title":"Comparative analysis of human bone marrow mesenchymal stem cells, articular cartilage derived chondroprogenitors and chondrocytes to determine cell superiority for cartilage regeneration","volume":"123","author":"Vinod","year":"2021","journal-title":"Acta Histochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/978-1-0716-2839-3_6","article-title":"Isolation and In Vitro Chondrogenic Differentiation of Human Bone Marrow-Derived Mesenchymal Stromal Cells","volume":"2598","author":"Armiento","year":"2023","journal-title":"Methods Mol. Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"942128","DOI":"10.3389\/fbioe.2022.942128","article-title":"Current applications of adipose-derived mesenchymal stem cells in bone repair and regeneration: A review of cell experiments, animal models, and clinical trials","volume":"10","author":"Zhang","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kulus, M., Sibiak, R., Stefa\u0144ska, K., Zdun, M., Wieczorkiewicz, M., Piotrowska-Kempisty, H., Ja\u015bkowski, J.M., Bukowska, D., Ratajczak, K., and Zabel, M. (2021). Mesenchymal Stem\/Stromal Cells Derived from Human and Animal Perinatal Tissues-Origins, Characteristics, Signaling Pathways, and Clinical Trials. Cells, 10.","DOI":"10.3390\/cells10123278"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Lee, D.H., Kim, S.A., Song, J.S., Shetty, A.A., Kim, B.H., and Kim, S.J. (2022). Cartilage Regeneration Using Human Umbilical Cord Blood Derived Mesenchymal Stem Cells: A Systematic Review and Meta-Analysis. Medicina, 58.","DOI":"10.3390\/medicina58121801"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Song, Y., and Jorgensen, C. (2022). Mesenchymal Stromal Cells in Osteoarthritis: Evidence for Structural Benefit and Cartilage Repair. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061278"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/jor.1100140502","article-title":"Contents and distributions of the proteoglycans decorin and biglycan in normal and osteoarthritic human articular cartilage","volume":"14","author":"Poole","year":"1996","journal-title":"J. Orthop. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"125","DOI":"10.4102\/jsava.v68i4.893","article-title":"An epizoological study of wastage in thoroughbred racehorses in Gauteng, South Africa","volume":"68","author":"Olivier","year":"1997","journal-title":"J. S. Afr. Vet. Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.2460\/ajvr.2001.62.1418","article-title":"Training failure among yearling horses","volume":"62","author":"Hernandez","year":"2001","journal-title":"Am. J. Vet. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1002\/art.23485","article-title":"Synovial fluid mesenchymal stem cells in health and early osteoarthritis: Detection and functional evaluation at the single-cell level","volume":"58","author":"Jones","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/scrt501","article-title":"Synovial fluid and synovial membrane mesenchymal stem cells: Latest discoveries and therapeutic perspectives","volume":"5","author":"Casado","year":"2014","journal-title":"Stem Cell Res. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1055\/s-0040-1710366","article-title":"Synovial fluid mesenchymal Stem Cells for knee arthritis and cartilage defects: A review of the literature","volume":"34","author":"Fang","year":"2021","journal-title":"J. Knee Surg."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e158450","DOI":"10.1172\/JCI158450","article-title":"Cellular senescence: A key therapeutic target in aging and diseases","volume":"132","author":"Zhang","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1038\/s41419-022-05089-w","article-title":"Extracellular vesicles enriched in connexin 43 promote a senescent phenotype in bone and synovial cells contributing to osteoarthritis progression","volume":"13","author":"Fonseca","year":"2022","journal-title":"Cell Death Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.ceb.2013.07.005","article-title":"Stressing the cell cycle in senescence and aging","volume":"25","author":"Chandler","year":"2013","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","article-title":"A biomarker that identifies senescent human cells in culture and in aging skin in vivo","volume":"92","author":"Dimri","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"138","DOI":"10.3389\/fcell.2020.00138","article-title":"Autophagy and Stem Cells: Self-Eating for Self-Renewal","volume":"8","author":"Chang","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"21485","DOI":"10.1002\/jcp.28895","article-title":"Autophagy and senescence: A new insight in selected human diseases","volume":"234","author":"Rajendran","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/bs.acr.2021.01.005","article-title":"Autophagy and senescence: Insights from normal and cancer stem cells","volume":"150","author":"Talukdar","year":"2021","journal-title":"Adv. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kang, H.T., Lee, K.B., Kim, S.Y., Choi, H.R., and Park, S.C. (2011). Autophagy impairment induces premature senescence in primary human fibroblasts. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023367"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"715200","DOI":"10.3389\/fcell.2021.715200","article-title":"Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action","volume":"9","author":"Chen","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1177\/1535370213493069","article-title":"Oxidative stress response elicited by mitochondrial dysfunction: Implication in the pathophysiology of aging","volume":"238","author":"Wang","year":"2013","journal-title":"Exp. Biol. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: An expanding universe","volume":"186","author":"Blasco","year":"2023","journal-title":"Cell"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"De Gaetano, A., Gibellini, L., Zanini, G., Nasi, M., Cossarizza, A., and Pinti, M. (2021). Mitophagy and Oxidative Stress: The Role of Aging. Antioxidants, 10.","DOI":"10.3390\/antiox10050794"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1001212","DOI":"10.3389\/fmolb.2022.1001212","article-title":"The role of oxidative stress in the development of knee osteoarthritis: A comprehensive research review","volume":"9","author":"Liu","year":"2022","journal-title":"Front. Mol. Biosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0049-0172(91)90018-U","article-title":"Oxygen radicals, inflammation, and arthritis: Pathophysiological considerations and implications for treatment","volume":"20","author":"Greenwald","year":"1991","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1002\/jcb.10428","article-title":"Differential roles of hydrogen peroxide and superoxide in mediating IL-1-induced NF-kappa B activation and iNOS expression in bovine articular chondrocytes","volume":"88","author":"Mendes","year":"2003","journal-title":"J. Cell Biochem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"151867","DOI":"10.1016\/j.acthis.2022.151867","article-title":"Senescent chondrogenic progenitor cells derived from articular cartilage of knee osteoarthritis patients contributes to senescence-associated secretory phenotype via release of IL-6 and IL-8","volume":"124","author":"Jacob","year":"2022","journal-title":"Acta Histochem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e12771","DOI":"10.1111\/acel.12771","article-title":"Expression of p16INK4a is a biomarker of chondrocyte aging but does not cause osteoarthritis","volume":"17","author":"Diekman","year":"2018","journal-title":"Aging Cell"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1080\/03008207.2016.1183667","article-title":"SOX9 and the many facets of its regulation in the chondrocyte lineage","volume":"58","author":"Lefebvre","year":"2017","journal-title":"Connect. Tissue Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Rim, Y.A., and Ju, J.H. (2020). The Role of Fibrosis in Osteoarthritis Progression. Life, 11.","DOI":"10.3390\/life11010003"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/OAJSM.S321139","article-title":"Cross-Communication Between Knee Osteoarthritis and Fibrosis: Molecular Pathways and Key Molecules","volume":"13","author":"Bolia","year":"2022","journal-title":"Open Access J. Sports Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1007\/BF02631122","article-title":"Reduction of proliferative heterogeneity of CHEF18 Chinese hamster cell line during the progression toward tumorigenicity","volume":"27","author":"Rainaldi","year":"1991","journal-title":"In Vitro Cell. Dev. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13045-016-0344-4","article-title":"Improving Nelarabine Efficacy in T Cell Acute Lymphoblastic Leukemia by Targeting Aberrant Pi3k\/Akt\/Mtor Signaling Pathway","volume":"9","author":"Lonetti","year":"2016","journal-title":"J. Hematol. Oncol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3109\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:24:28Z","timestamp":1760120668000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,4]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043109"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043109","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,4]]}}}