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The occurrence and progress of osteoporosis(OP)are partially caused by impaired osteoblast differentiation.Interleukin-I receptor antagonist(IL1RN)is an immune modulatory molecule that commonly functions by means of competing the binding site of IL-1R with IL-1.Although it was recently reported that IL1RN is involved in osteoblast differentiation,the role of IL1RN in osteo-genesis remains unclear.In this work,we first investigated the expression pattern of IL1RN in ovariectomy mice and in vitro osteogenic induction of MC3T3-E1 and C3H10T1/2 cells.To verify the exact role of IL1RN in osteoblast differentiation,we established IL1RN-downregulated/upregulated cell lines.The results indicated that IL1RN was constantly expressed in MC3T3-E1 and C3H10T1/2 cells.Interestingly,an increase of IL1RN expression in osteoblasts occurred when osteoblasts were cultured in osteogenic medium(OM).As expected,silencing of IL1RN attenuated the osteogenic effect of OM,while IL1RN overexpression increased the osteogenic staining and promoted the expression of osteogenic markers,including alkaline phosphatase,osterix,and osteocalcin.In addition to evaluating the function of IL1RN in osteoblasts,we also investigated the molecular mechanism of the role of IL1RN in osteoblasts.We found that IL1RN interacts with integrin β3 to activate β-catenin signaling,which finally regulates osteoblast differentiation.Taken together,this study provides the framework that IL1RN,as a novel regulator of osteogenesis,may be a potential therapeutic target for the treatment of OP.