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The capability of mesenchymal stem cells (MSCs) to repair bone damage and defects has long been investigated. The receptor activator of nuclear factorkappa B (RANK), its ligand (RANKL) and the decoy receptor osteoprotegerin (OPG) axis is crucial to keep the equilibrium between osteoblastic and osteoclastic activity. Exendin‐4 utilization increased bone formation and enhanced bone integrity. This study aimed to investigate the mentioned axis and determine the effect of exendin‐4 upon adipose mesenchymal stem cells (Ad‐MSCs) osteogenic differentiation. Ad‐MSCs were isolated from rat epididymal fat, followed by characterization and then differentiation into osteocytes both in the presence or absence of exendin‐4. Osteogenic differentiation was evaluated by alizarin red staining and the expression of osteogenic markers; using reverse transcriptase‐quantitative polymerase chain reaction, western blotting and enzyme‐linked immunoassay. MSCs derived from rat epididymal fat were isolated and characterized, along with their differentiation into osteocytes. The differentiated cells were alizarin redstained, showing increased staining intensity upon addition of exendin‐4. Moreover, the addition of exendin‐4 elevated the messenger RNA expression levels of osteogenic markers; runt‐related transcription factor‐2 (RUNX‐2), osteocalcin, and forkhead box protein O‐1 while reducing the expression of the adipogenic marker peroxisome‐proliferator‐activated receptor‐gamma. Exendin‐4 addition elevated OPG levels in the supernatant of osteogenic differentiated cells. Moreover, exendin‐4 elevated the protein levels of glucagon‐like peptide‐1 receptor and RUNX‐2, while decreasing both RANK and RANKL. In conclusion, osteogenic differentiation of Ad‐MSCs is associated with increased osteoblastic rather than osteoclastic activity.



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