- Human bone marrow-derived mesenchymal stem cells (hMSCs) are promising candidates for cellular therapy owing to their multipotency to differentiate into several cell lineages. Elucidating the signaling events involved in the response of hMSCs to diverse stimulants affecting their differentiation may considerably promote their clinical use. In this study, we attempted to illuminate the molecular signaling networks involved in bone morphogenetic protein (BMP)-stimulated hMSC osteogenic differentiation. We demonstrate that eradication of signal transducers and activators of transcription (STAT) signaling considerably enhances BMP-induced osteogenic differentiation of hMSCs. BMP 2 and 4 are shown for the first time to activate the Janus-activated kinase (JAK)-STAT pathway in hMSC. Specifically, we reveal that JAK2 mediates STAT3 tyrosine phosphorylation in response to the two BMPs, whereas BMP2- and BMP4-induced STAT3 serine phosphorylation involves two divergent cascades, namely the mTOR and ERK1/2 cascades, respectively. Furthermore, elimination of the STAT3 signaling pathway by the inhibitors, AG490 or STAT3 siRNA, results in the acceleration and augmentation of BMPs-induced osteogenic differentiation, thus proposing a role for JAK-STAT signaling as a negative regulator of this process in MSCs. We believe that the findings presented in this study may be the basis for the development of a useful strategy to better control stem cell fate through intervention in molecular signaling networks. Hopefully, such a strategy will include the development of more efficient and controllable protocols for hMSC differentiation and facilitate their use in regenerative medicine.