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Recent studies revealed that sequential release of bone morphogenetic protein 2 and insulin-like growth factor 1 plays an important role in osteogenic process, suggesting that cytokines bone morphogenetic protein 2 and insulin-like growth factor 1 function in a time-dependent manner. However, the specific molecular mechanisms underlying these observations remained elusive, impeding the elaborate manipulation of cytokine sequential delivery in tissue repair. The aim of this study was to identify the key relevant pathways and processes regulating bone morphogenetic protein 2/insulin-like growth factor 1-mediated osteoblastic differentiation. Based on the microarray and proteomics data, and differentiation/growth status of mouse bone marrow stromal cells, we constructed a multiscale systems model to simulate the bone marrow stromal cells lineage commitment and bone morphogenetic protein 2 and insulin-like growth factor 1-regulated signaling dynamics. The accuracy of our model was validated using a set of independent experimental data. Our study reveals that, treatment of bone marrow stromal cells with bone morphogenetic protein 2 prior to insulin-like growth factor 1 led to the activation of transcription factor Runx2 through TAK1-p38 MAPK and SMAD1/5 signaling pathways and initiated the lineage commitment of bone marrow stromal cells. Delivery of insulin-like growth factor 1 four days after bone morphogenetic protein 2 treatment optimally activated transcription factors osterix and β-catenin through ERK and AKT pathways, which are critical to preosteoblast maturity. Our systems biology approach is expected to provide technical and scientific support in optimizing therapeutic scheme to improve osteogenesis/bone regeneration and other essential biological processes.

A systems biology approach to studying the molecular mechanisms of osteoblastic differentiation under cytokine combination treatment