Indomethacin promotes adipogenesis of mesenchymal stem cells through a cyclooxygenase independent mechanism.
Regulation of mesenchymal stem cell (MSC) lineage selection is important for the generation of bone mass. Inhibition of cyclooxygenase-2 (COX2) may increase adipogenesis at the cost of decreasing osteoprogenitor output. Here we investigated the role of COX2 and its products during MSC differentiation. Indomethacin stimulated adipogenesis (increased aP2, adiponectin and lipid droplets) of CH310T1/2 stem cells as well as marrow-derived MSCs to a degree similar to the PPARγ2 ligand, rosiglitazone. Unlike rosiglitazone, indomethacin significantly upregulated PPARγ2 expression. Indomethacin and the COX2 specific inhibitor celecoxib suppressed PGE2 production, but celecoxib did not induce adipogenesis. As well, addition of PGE2 failed to reverse indomethacin induced adipogenesis, indicating that indomethacin's effects were prostaglandin independent. In MSCs over-expressing PPARγ2 and RXRα, indomethacin did not increase PPAR-induced transcription, while rosiglitazone and 15d-PGJ2 did (1.7- and 1.3-fold, respectively, P < 0.001). We considered whether indomethacin might directly affect C/EBPβ proximally to PPARγ2 induction. Indomethacin significantly increased C/EBPβ expression and protein within 24 h of addition. These results indicate that indomethacin promotes adipogenesis by increasing C/EBPβ and PPARγ2 expression in a prostaglandin-independent fashion. This effect of indomethacin is pertinent to potential deleterious effects of this commonly used anti-inflammatory drug on bone remodeling and tissue healing.
Styner
Maya
M
Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7170, USA. mstyner@med.unc.edu
Sen
Buer
B
Xie
Zhihui
Z
Case
Natasha
N
Rubin
Janet
J
D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D000068579:Celecoxib; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology*; D008024:Ligands; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D020218:Response Elements / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D008024:Ligands; D047495:PPAR gamma; D011720:Pyrazoles; D013449:Sulfonamides; D051176:beta Catenin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D007213:Indomethacin