Histamine H-1, H-2, and H-3 receptors are expressed by osteoblastic MC3T3-E1 (E1) cells derived from mouse calvaria. Expression of the osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) transcript was induced in E1 cells and bone marrow stromal cells (ST2). Histamine markedly increased the steady-state level of ODF/RANKL mRNA in a dose-dependent manner. The effect of histamine on expression of ODF/RANKL mRNA by E1 cells was transient, with a peak at 6 h. Western blot analysis revealed that histamine increased production of ODF/RANKL protein by E1 cells at 12 h. In cocultures of E1 cells and mouse bone marrow cells, histamine stimulated osteoclastogenesis in the presence of 1,25-dihydroxyvitamin D-3 and this effect was blocked by preincubation with neutralizing antibody against ODF/RANKL. These results suggest that histamine regulates osteoclastogenesis, at least in part, through induction of ODF/RANKL expression by osteoblasts and bone marrow stromal cells. (C) 2002 Elsevier Science (USA). All rights reserved.