Using human osteoblastic SaM-1 cells, we investigated the effects of lysophosphatidic acid (LPA) on the production of interleukin (IL)-6 and IL-8, molecules which are capable of stimulating the development of osteoclasts from their haematopoietic precursors, and examined the signal transduction systems involved in their effect on these cells. These human osteoblasts constitutively expressed endothelial differentiation genes (Edg)-2 and Edg-4, which are LPA receptors. LPA increased gene and protein expression of IL-6 and IL-8 in SaM-1 cells. The expression of IL-6 and IL-8 mRNAs was maximal at 1-3h, and the increase in IL-6 and IL-8 synthesis in response to lysophosphatidic acid (1-10 microM) occurred in a concentration-dependent manner. These increases were blocked by Ki16425, an Edg-2/7 antagonist. In addition, LPA caused an increase in the intracellular Ca(2+) concentration ([Ca(2+)](i)), which was inhibited by pretreatment with Ki16425 or 2-aminoethoxy-diphenylborate (2-APB), an inositol 1,4,5-triphosphate (IP(3)) receptor (IP(3)R) blocker. The pretreatment of SaM-1 cells with U-73122, a phospholipase C (PLC) inhibitor, and 2-APB also inhibited the increase in IL-6 and IL-8 synthesis in response to LPA. These findings suggest that extracellular LPA-induced IL-6 and IL-8 synthesis occurred through Edg-2 (LPA(1) receptor) and the activation of PLC and IP(3)-mediated intracellular calcium release in SaM-1 cells.