Abstract: Objective To determine the effect of fibroblast growth factor-21（FGF-21）on the osteogenic differention of human bone mesenchymal stem cells (hBMSCs) exposed to a hyperglycemia condition in vitro. Methods hBMSCs were isolated from adult bone marrows, and identified by Alizarin red and oil red O staining. The expressions of immunophenotype were analysed using flow cytometry (CD105, CD90, CD73, CD44).HBMSCs were divided into control group 〔glucose (Glu) concentration of 5.5 mmol/L〕, Glu A, B, C groups (Glu 16.5, 25, 40 mmol/L), FGF-21 group (Glu 5.5mmol/ L+ FGF-21 ),Glu B+ FGF-21 group, and Glu B +FGF-21+cell mitogen activated protein kinase (MAPK) blocker (PD98059, SP600125 ,and SB203580) groups. The effect of FGF-21 on the differentiation of hBMSCs was detected using indicators as follows: alkaline phosphatase （ALP） on day 14, mRNA expressions ofALP, osteocalcin（OCN）and Runx2, protein expressions and phosphorylation of extracellular signal regulated kinase （ERK）, mitogen-activated protein kinase（P38） and c-Jun N-terminal kinases（JNK） on day 21. Results ①hBMSCs differentiated into osteoblast cells and lipocyte. The hBMSCs were identified by flow cytometry. ②Compared with control group, significant increases of ALP mRNA, OCN mRNA and Runx2mRNA levels, as well as phosphorylation of ERK, P38 and JNK were observed in Glu A, B, C groups. ③Compared with Glu B group, ALP, OCN and Runx2 mRNA levels, and phosphorylation of ERK, P38 and JNK were decreased in Glu B+FGF-21 group . ④Compared with Glu B+FGF-21 group, ALP and Runx2 mRNA levels, and phosphorylation of ERK, JNK and P38 were decreased in Glu B +FGF-21 +MAPK blocker groups. Conclusion High glucose could promote the biomineralization of hBMSCs. FGF-21 in high glucose environment could inhibit the osteogenic differentiation of hBMSCs.