The simple glycerophospholipid lysophosphatidic acid (LPA) acts both as an intermediary in phospholipid metabolism and as an intercellular signaling molecule in its own right. In various cell types, LPA signals through its membrane-bound, G protein-coupled receptors to influence cellular processes such as proliferation, survival, and cytoskeletal function. Its actions in bone cells have not been studied. Here we show that the LPA receptor, LP(A1)/edg-2/vzg-1, is expressed in primary rat osteoblasts and the UMR 106-01 osteoblastic cell line. LPA potently induces DNA synthesis and an increase in cell number in cultures of osteoblastic cells. LPA rapidly (within 10 min) stimulates phosphorylation of p42/44 mitogen-activated protein (MAP) kinases in osteoblastic cells, an effect that is sensitive to inhibition of G(i) proteins, inhibition of influx of extracellular calcium, and inhibition of protein kinase C. LPA-induced DNA synthesis is partially inhibited by either pertussis toxin or calphostin C, but is insensitive to specific inhibitors of MEK, the kinase upstream of p42/44 MAP kinases, or of phosphatidylinositol-3 kinases. These data demonstrate that LPA is an osteoblast mitogen whose signaling effects in osteoblastic cells include activation of p42/44 MAP kinases. However, the LPA mitogenic signal in osteoblastic cells, while requiring G(i) proteins and protein kinase C, is independent of the activity of p42/44 MAP kinases.