AbstractParathyroid hormone (PTH), an anabolic agent for bone metabolism, has profound effects on gene expression in the osteoblast. Recently, we identified that amphiregulin (AR), an EGF‐like ligand, is an immediate early gene for PTH treatment and has an important role in bone metabolism. In the present report, by using different PTH peptide fragments, protein kinase activators, and inhibitors, we have demonstrated that PTH regulates amphiregulin in a cAMP‐protein kinase A (PKA)‐dependent manner both in vitro and in vivo. We found that the phosphorylation of cAMP‐response element (CRE)‐binding protein (CREB) preceded AR transcription after PTH treatment. Moreover, luciferase reporter assays revealed that the binding of phosphorylated CREB to a conserved CRE site in the AR promoter plays an important role in basal, PTH‐induced, and prostaglandin E2 (PGE2)‐induced AR expression in osteoblastic cells. In summary, our data suggest that PTH‐induced AR mRNA expression is mediated primarily through cAMP‐PKA‐CREB signaling. © 2005 Wiley‐Liss, Inc.