Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, mediates a multitude of (patho)physiological events including activation of mitogen-activated protein kinases (MAPKs). As LPA may induce cellular reponses in human osteosarcoma, the present study aimed at investigating expression of various LPA receptors, LPA-mediated activation of MAPK via G-protein coupling, and expression of early response genes in a cellular model for human osteosarcoma. We show that MG-63 cells express three members of the endothelial differentiation gene (Edg) family of G-protein coupled receptor transcripts (LPA(1-3)) but only two (LPA(4/5)) out of three members of the non-Edg family LPA receptor transcripts. Stimulation of MG-63 cells with LPA or synthetic LPA receptor agonists resulted in p42/44 MAPK phosphorylation via LPA(1)-LPA(3) receptors. Using pharmacological inhibitors, we show that LPA-mediated phosphorylation of p42/44 MAPK by LPA receptor engagement is transmitted by G(αi)-dependent pathways through the Src family of tyrosine kinases. As a consequence, a rapid and transient upregulation of the zinc finger transcription factor early growth response-1 (Egr-1) was observed. Egr-1 expression was strictly mediated via G(αi)/Src/p42/44 MAPK pathway; no involvement of the G(αq/11)/PLC/PKC or the PLD/PI3 kinase/Akt pathways was found. LPA-induced expression of functional Egr-1 in MG-63 cells could be confirmed by electrophoretic mobility shift assay. LPA-induced Egr-1 upregulation was accompanied by a time-dependent decrease of periostin (previously called osteoblast-specific factor 2), a cell adhesion protein for pre-osteoblasts. Silencing of LPA(1) and/or Egr-1 in MG-63 cells reversed LPA-mediated suppression of periostin. We here demonstrate a crosslink between Egr-1 and periostin in cancer cells, in particular in human osteosarcoma.