Synovial fibroblasts, established in culture from patients with RA, were treated with proinflammatory cytokines and prostaglandin E(2) (PGE(2)) for 24 h. These cells enhanced the production and the messenger RNA expression of PTH-related peptide (PTHrP) using proinflammatory cytokines, such as interleukin (IL)-1alpha, tumor necrosis factor-alpha without the coordination of other cytokines. In addition, PGE(2) which has been induced with IL-1, also enhanced the production of PTHrP. The IL-1alpha-induced PTHrP production was inhibited by PG H synthetase (Cox) inhibitors, indomethacin, and also by Cox-2 inhibitor, NS398. The synovial fibroblasts expressed PGE(2) receptor subtypes, EP2, EP3, EP4, but not EP1, as detected by RT-PCR. Of the PGE(2) receptor agonists, EP4 agonist showed the most marked induction of PTHrP, and EP2 agonist partly induced the production. However, these PGE(2) receptors were not induced by the treatment with IL-1alpha and PGE(2). These results suggest that induction of PGE(2) by IL-1alpha may be an important component of the PTHrP production of the inflammatory process in synovial tissues from patients with RA. These findings are the first to demonstrate that PGE(2) stimulates PTHrP production, which is mediated mostly by EP2 and EP4 receptors.