POEM, also known as nephronectin, is an extracellular matrix protein considered to be a positive regulator of osteoblast differentiation. In the present study, we found that tumor necrosis factor-alpha (TNF-alpha), a key regulator of bone matrix properties and composition that also inhibits terminal osteoblast differentiation, strongly inhibited POEM expression in the mouse osteoblastic cell line MC3T3-E1. TNF-alpha-induced down-regulation of POEM gene expression occurred in both time- and dose-dependent manners through the nuclear factor kappa B (NF-kappa B) pathway. In addition, expressions of marker genes in differentiated osteoblasts were down-regulated by TNF-alpha in a manner consistent with our findings for POEM, while over-expression of POEM recovered TNF-alpha-induced inhibition of osteoblast differentiation. These results suggest that TNF-alpha inhibits POEM expression through the NF-kappa B signaling pathway and down-regulation of POEM influences the inhibition of osteoblast differentiation by TNF-alpha. (C) 2011 Elsevier Inc. All rights reserved.