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Fluid shear stress (FSS) and estrogen exposure positively regulate bone metabolism. Fibroblast growth factor receptor 1 (FGFR1) plays a vital role in FSS-induced osteogenesis. An in vitro experiment with MC3T3-E1 cells combined with microarray analysis aided us in identification of the genes differentially expressed in response to FSS and highlighted the role of FGFR1 in this process. Both estrogen exposure and FSS increase methyl thiazol tetrazolium (MTT) values and alkaline phosphatase (ALP) activity, as well as the levels of Runt-related transcription factor 2 (Runx2) and osteocalcin (OCN). The effects of estrogen exposure and FSS were cumulative. Treatment with PD166866 inhibitor of the FGFR1 reduced the MTT values, increased ALP activity, and increased the levels of Runx2 and OCN. To investigate the regulation of FGFR1 signaling in stressed cells, a number of key components of the mitogen-activated protein kinase (MAPK) cascade were quantitatively examined. Neither estrogen nor FSS change the protein expression of extracellular signal-regulated kinase (ERK), Jun amino-terminal kinases (JNK) or p38, but positively influence their phosphorylation levels. Treatment with the FGFR1 inhibitor induced an increase in ERK phosphorylation levels only. In summary, estrogen exposure and FSS have a synergistic effect in osteogenesis. FGFR1 promotes osteoblast proliferation and inhibits the differentiation of osteoblasts. In MC3T3-E1 cells, FGFR1 signaling responds to independent and combined effects of estrogen and FSS. MAPK cascades participate in osteogenesis, but only the ERK signaling pathway responds to FGFR1.