Runx2 is a key regulator of osteoblast-specific gene expression and controls the expression of multiple target genes during osteoblast differentiation. Although some transcriptional targets for Runx2 are known, it is believed that the osteogenic action of Runx2 is mediated by additional target genes, and increasing studies are performed in order to identify such Runx2-responsive genes. To identify genes following the inhibition of Runx2 in osteoblastic cell line, SaOs-2 was stably transfected with a dominant negative mutant of Runx2 (Deltacbfa1) under the control of a strong promoter. Comparison of gene expression patterns by differential display on selected SaOs-2 clones allowed us to observe that GNAS mRNA which encodes for the Gsalpha protein is overexpressed (5 to 8 fold) in cells presenting high levels of Deltacbfa1. This overexpression was also observed at the protein level and seemed to be reflected by an increased basal cAMP level. Gel shift experiments performed in this study indicate that Runx2 is able to bind to the promoter of GNAS, suggesting a direct regulation at the transcriptional level. Well-described GNAS mutations like fibrous dysplasia or Albright hereditary osteodystrophy are linked to abnormality in osteoblast function, and numerous evidences showed that Gsalpha coupled adrenergic receptors increase the expression of osteotrophic factors and regulate bone mass. Regulation of Gsalpha protein by Runx2 seems to be of particular interest considering the increasing evidences on bone metabolism regulation by G proteins.