Inflammatory bone diseases are characterized by the presence of pro-inflammatory cytokines that regulate bone turnover. Osteoprotegerin (OPG) is a soluble osteoblast-derived protein that influences bone resorption by inhibiting osteoclast differentiation and activation. In the present study, we demonstrate that interleukin-1beta (IL-1beta) and tumor necrosis factor alpha induce OPG mRNA production and OPG secretion by osteoblast-like MG-63 cells. Maximum induction of OPG secretion by either cytokine requires activation of the p38 mitogen activated protein kinase (MAPK) pathway but neither the p42/p44 (ERK) nor the c-Jun N-terminal MAPK pathways. Induction of OPG mRNA by either cytokine is also p38 MAPK dependent. Taken together, these data indicate that cytokine-induced OPG gene expression and protein secretion are differentially regulated by specific MAP kinase signal transduction pathways. (C) 2005 Elsevier Inc. All rights reserved.