Lipopolysaccharide (LPS) is a critical component of the outer membrane of Gram—negative bacteria. Many cellular signals that are activated by Gram—negative bacteria are initiated by LPS. LPS triggers not only inflammatory responses, but also activates pro—apoptotic signals in a series of human cell types. However, there is relatively minimal data on the microRNA—dependent mechanism(s) of LPS—induced functional activity in osteoblast cells. CCK—8 assay and flow cytometry were used to measure cell viability and apoptosis, respectively. RT—PCR and western blot were performed to determine the mRNA and protein expression in osteoblast cells. In this study, we found that LPS triggered apoptosis in osteoblastic hFOB1.19 cells and induced a low expression of the miRNA—21. Furthermore, through the gene microarray technique, OAS1 was screened and later confirmed to be the target gene which was up—regulated in response to the low expression of miRNA—21. Knockdown of OAS1 by specific siRNAs significantly rescued the LPS—induced hFOB1.19 cell apoptosis. Our data suggest that LPS induces low expression of miRNA—21which consequently causes the up—regulation of the downstream gene OAS1 and eventually triggers apoptosis in hFOB1.19 cells. Knockdown of OAS1 rescues LPS—induced cell death and thus may be a promising therapeutic strategy for orthopedic diseases.