{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T04:57:18Z","timestamp":1788584238149,"version":"build-2803163510"},"reference-count":51,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["P2022TKYNN"],"award-info":[{"award-number":["P2022TKYNN"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["2022CAKEW9"],"award-info":[{"award-number":["2022CAKEW9"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]},{"award":["P2022TKYNN"],"award-info":[{"award-number":["P2022TKYNN"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"award":["2022CAKEW9"],"award-info":[{"award-number":["2022CAKEW9"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Osteoporosis is an age-related metabolic bone disorder characterized by an imbalance between bone resorption and formation. Natural polyphenols have gained attention as potential complementary strategies for its prevention. In this study, we investigated the effects of a sustainable, polyphenol-rich extract from red grape pomace (GPE) on human mesenchymal stem cell (MSC) fate and its underlying mechanisms of action. We found that GPE significantly promoted osteogenic differentiation while suppressing adipogenic differentiation in canonical bone marrow-derived MSCs (BMSCs). This biological effect was preserved in adipose tissue-derived MSCs (AdMSCs) obtained from elderly patients (&gt;65 years) at high cardiovascular risk. Mechanistically, GPE downregulated adipogenic markers (PPAR\u03b3, CD36 and FABP4) and enhanced osteogenic markers (RUNX2, ALP, OSX, BMP-2, OPN, COL1A1 and OCN). Moreover, GPE activated NRF2-dependent redox signaling, as evidenced by increased NRF2 nuclear translocation and transcriptional activity. Accordingly, GPE treatment significantly upregulated, or consistently increased, the expression of multiple NRF2 target genes, including HO-1, GPX, CAT, GCLC, and NQO1. Importantly, pharmacological inhibition of NRF2 attenuated GPE-induced ALP activity, confirming NRF2 as a key mediator of its osteogenic effects. Overall, grape pomace-derived polyphenols act as upstream modulators of redox-sensitive and osteogenic transcription factors, rebalancing MSC differentiation toward osteogenesis and mitigating age-related bone fragility.<\/jats:p>","DOI":"10.3390\/biology15090719","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T10:15:27Z","timestamp":1777630527000},"page":"719","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Grape Pomace Polyphenolic Extract Promotes Osteogenic Differentiation in Human Mesenchymal Stem Cells Through Activation of RUNX2 and NRF2 Transcription Factors: A Potential Natural Strategy for Osteoporosis Prevention"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0726-2081","authenticated-orcid":false,"given":"Nadia","family":"Calabriso","sequence":"first","affiliation":[{"name":"Institute of Clinical Physiology (IFC), National Research Council (CNR), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marika","family":"Massaro","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology (IFC), National Research Council (CNR), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1589-4177","authenticated-orcid":false,"given":"Stefano","family":"Quarta","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology (IFC), National Research Council (CNR), 73100 Lecce, Italy"},{"name":"Department of Experimental Medicine (DiMeS), University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6890-3674","authenticated-orcid":false,"given":"Luisa","family":"Siculella","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine (DiMeS), University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4913-9834","authenticated-orcid":false,"given":"Giuseppe","family":"Santarpino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, Magna Graecia University of Catanzaro, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4983-2767","authenticated-orcid":false,"given":"Tiziano","family":"Verri","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Sciences and Technologies (DISTEBA), University of Salento, 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmela","family":"Gerardi","sequence":"additional","affiliation":[{"name":"Institute of Sciences of Food Production (ISPA), National Research Council (CNR), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0608-9600","authenticated-orcid":false,"given":"Giovanna","family":"Giovinazzo","sequence":"additional","affiliation":[{"name":"Institute of Sciences of Food Production (ISPA), National Research Council (CNR), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8307-1829","authenticated-orcid":false,"given":"Maria Annunziata","family":"Carluccio","sequence":"additional","affiliation":[{"name":"Institute of Clinical Physiology (IFC), National Research Council (CNR), 73100 Lecce, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1001\/jama.2025.6003","article-title":"Osteoporosis: A Review","volume":"334","author":"Morin","year":"2025","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Aibar-Almaz\u00e1n, A., Voltes-Mart\u00ednez, A., Castellote-Caballero, Y., Afanador-Restrepo, D.F., Carcel\u00e9n-Fraile, M.D.C., and L\u00f3pez-Ruiz, E. 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