{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T11:07:12Z","timestamp":1768734432821,"version":"3.49.0"},"reference-count":27,"publisher":"S. Karger AG","issue":"2","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"},{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.karger.com\/Services\/SiteLicenses"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells Tissues Organs"],"published-print":{"date-parts":[[2016]]},"abstract":"<jats:p>Growth factors are crucial regulators of cell differentiation towards tissue and organ development. Insulin and transforming growth factor-\u03b2 (TGF-\u03b2) have been used as the major factors for chondrogenesis in vitro, by activating the AKT and Smad signaling pathways. Previous reports demonstrated that AKT and Smad3 have a direct interaction that results in the inhibition of TGF-\u03b2-mediated cellular responses. However, the result of this interaction between AKT and Smad3 during the chondrogenesis of human bone marrow-derived stem\/progenitor cells (hBMSCs) is unknown. In this study, we performed functional analyses by inducing hBMSCs into chondrogenesis with insulin, TGF-\u03b23 or in combination, and found that TGF-\u03b23, when applied concomitantly with insulin, significantly decreases an insulin-induced increase in mRNA levels of the master regulator of chondrogenesis, &lt;i&gt;SOX9&lt;\/i&gt;, as well as the regulators of the 2 major chondrocyte markers, &lt;i&gt;ACAN&lt;\/i&gt; and &lt;i&gt;COL2A1&lt;\/i&gt;. Similarly, the insulin\/TGF-\u03b23-treated group presented a significant decrease in the deposition of cartilage matrix as detected by safranin O staining of histological sections of hBMSC micromass cultures when compared to the group stimulated with insulin alone. Intracellular analysis revealed that insulin-induced activation of AKT suppressed Smad3 activation in a dose-dependent manner. Accordingly, insulin\/TGF-\u03b23 significantly decreased the TGF-\u03b23-induced increase in mRNA levels of the direct downstream factor of TGF-\u03b2\/Smad3, CCN2\/CGTF, compared to the group stimulated with TGF-\u03b23 alone. On the other hand, insulin\/TGF-\u03b23 stimulation did not suppress insulin-induced expression of the downstream targets TSC2 and DDIT4\/REDD1. In summary, insulin and TGF-\u03b23 have antagonistic effects when applied concomitantly, with a minimal number of factors. The application of an insulin\/TGF-\u03b23 combination without further supplementation should be used with caution in the chondrogenic differentiation of hBMSCs.<\/jats:p>","DOI":"10.1159\/000442411","type":"journal-article","created":{"date-parts":[[2016,2,11]],"date-time":"2016-02-11T22:01:16Z","timestamp":1455228076000},"page":"88-96","source":"Crossref","is-referenced-by-count":10,"title":["Antagonistic Effects of Insulin and TGF-\u03b23 during Chondrogenic Differentiation of Human BMSCs under a Minimal Amount of Factors"],"prefix":"10.1159","volume":"201","author":[{"given":"Emilio Satoshi","family":"Hara","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mitsuaki","family":"Ono","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuya","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junji","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuri","family":"Hazehara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hai Thanh","family":"Pham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuo","family":"Kuboki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"127","published-online":{"date-parts":[[2016,2,12]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","DOI":"10.1007\/s10165-008-0048-x"},{"key":"ref2","doi-asserted-by":"publisher","DOI":"10.1006\/excr.2001.5278"},{"key":"ref3","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1117"},{"key":"ref4","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413913200"},{"key":"ref5","doi-asserted-by":"publisher","DOI":"10.1002\/jbmr.2502"},{"key":"ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2012.10.016"},{"key":"ref7","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00505"},{"key":"ref8","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(88)90339-9"},{"key":"ref9","doi-asserted-by":"publisher","DOI":"10.1159\/000153041"},{"key":"ref10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2443.2008.01209.x"},{"key":"ref11","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2014.01.009"},{"key":"ref12","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.051213"},{"key":"ref13","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0024546"},{"key":"ref14","doi-asserted-by":"publisher","DOI":"10.1093\/jb\/mvr089"},{"key":"ref15","doi-asserted-by":"publisher","DOI":"10.1159\/000313399"},{"key":"ref16","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.10113"},{"key":"ref17","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2006.02.002"},{"key":"ref18","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1113"},{"key":"ref19","doi-asserted-by":"publisher","DOI":"10.1038\/nrrheum.2012.98"},{"key":"ref20","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M310412200"},{"key":"ref21","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2010.05.026"},{"key":"ref22","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304583200"},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.1089\/ten.tea.2007.0252"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00966.2011"},{"key":"ref25","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-013-0204-8"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1002\/art.38912"},{"key":"ref27","doi-asserted-by":"publisher","DOI":"10.1007\/s10529-010-0293-x"}],"container-title":["Cells Tissues Organs"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/442411","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.karger.com\/Article\/Pdf\/442411","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T18:08:57Z","timestamp":1745431737000},"score":1,"resource":{"primary":{"URL":"https:\/\/karger.com\/article\/doi\/10.1159\/000442411"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2016,3,1]]}},"URL":"https:\/\/doi.org\/10.1159\/000442411","archive":["Portico"],"relation":{"is-supplemented-by":[{"id-type":"doi","id":"10.6084\/m9.figshare.5129113","asserted-by":"subject"}]},"ISSN":["1422-6405","1422-6421"],"issn-type":[{"value":"1422-6405","type":"print"},{"value":"1422-6421","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016]]}}}