{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T19:52:50Z","timestamp":1762458770258},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[1996,12,1]],"date-time":"1996-12-01T00:00:00Z","timestamp":849398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"NIH","award":["(DE08681 to K-HWL)"],"award-info":[{"award-number":["(DE08681 to K-HWL)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[1996,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We have recently demonstrated that phenytoin, a widely used therapeutic agent for seizure disorders, has osteogenic effects in rats and in humans in vivo, and in human bone cells in vitro. The goal of the present study was to determine the mechanism of the osteogenic action of phenytoin in normal human mandible-derived bone cells. Because many osteogenic agents increased bone cell proliferation through mediation by growth factors, we tested the hypothesis that the osteogenic effects of phenytoin involved the release of a growth factor by measuring the mRNA level of several bone cell growth factors and insulin-like growth factor (IGF) binding proteins with Northern blots using specific cDNA probes. Treatment with 5\u201350 \u03bcM phenytoin reproducibly and markedly increased (up to 6-fold, p &amp;lt; 0.001) the mRNA of transforming growth factor (TGF)-\u03b21, but not that of other growth factors (i.e., IGF-II, platelet-derived growth factor-A [PDGF-A], PDGF-B, and TGF-\u03b22) and IGF binding proteins (i.e., IGFBP-3, \u22124, and \u22125). The stimulation was dose dependent, with an optimal dose of 10\u201350 \u03bcM. Maximal increase was seen after 1 h of phenytoin treatment. The release of biologically active TGF-\u03b2 activity in conditioned media was measured with the mink lung cell proliferation inhibition assay. Twenty-four hours of phenytoin treatment significantly increased the production of biologically active TGF-\u03b2 (2-fold, p &amp;lt; 0.05) with the optimal dose between 5\u201350 \u03bcM. Comparisons between the in vitro osteogenic effects of phenytoin and those of TGF-\u03b21 reveal that these two agents at their respective optimal doses had similar maximal stimulatory effects on [3H]thymidine incorporation, alkaline phosphatase (ALP)-specific activity, and type I\u03b1-2 collagen mRNA expression in human bone cells. The stimulatory effects of phenytoin on [3H]thymidine incorporation and ALP-specific activity were completely blocked by a neutralizing anti-TGF-\u03b2 antibody. In conclusion, these findings demonstrate for the first time that at least some of the osteogenic actions of phenytoin in human bone cells could be in part mediated by TGF-\u03b21.<\/jats:p>","DOI":"10.1002\/jbmr.5650111208","type":"journal-article","created":{"date-parts":[[2010,2,24]],"date-time":"2010-02-24T19:24:02Z","timestamp":1267039442000},"page":"1880-1888","source":"Crossref","is-referenced-by-count":14,"title":["Osteogenic actions of phenytoin in human bone cells are mediated in part by TGF-\u03b21"],"prefix":"10.1093","volume":"11","author":[{"given":"Osamu","family":"Nakade","sequence":"first","affiliation":[{"name":"Department of Oral Pathology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan"},{"name":"Departments of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit, Jerry L. Pettis Memorial V.A. Medical Center, Loma Linda, California, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J.","family":"Baylink","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit, Jerry L. Pettis Memorial V.A. Medical Center, Loma Linda, California, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.-H. William","family":"Lau","sequence":"additional","affiliation":[{"name":"Departments of Medicine and Biochemistry, Loma Linda University, and Mineral Metabolism Unit, Jerry L. Pettis Memorial V.A. 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