Nephronectin (Npnt), also called POEM, is an extracellular matrix protein considered to play critical roles as an adhesion molecule in the development and functions of various tissues, such as the kidneys, liver, and bones. In the present study, we examined the molecular mechanism ofNpnt gene expression and found that oncostatin M (OSM) strongly inhibitedNpnt mRNA expression in MC3T3‐E1 cells from a mouse osteoblastic cell line. OSM also induced a decrease inNpnt expression in both time‐ and dose‐dependent manners via both the JAK/STAT and MAPK pathways. In addition, OSM‐induced inhibition of osteoblast differentiation was recovered by over‐expression ofNpnt. These results suggest that OSM inhibitsNpnt expression via the JAK/STAT and MAPK pathways, while down‐regulation ofNpnt by OSM influences inhibition of osteoblast differentiation.