Helodermin belongs to the VIP family of polypeptides. Recent in vivo data suggest that helodermin-like peptides might be involved in the regulation of calcium metabolism. We show that helodermin specifically binds to a secretin-type receptor in osteoblast-like cells from fetal rat calvaria and increases the basal and PTH-stimulated cAMP concentration of these cells. In organ cultures of fetal rat calvaria, helodermin strongly inhibits bone matrix apposition and augments PTH-induced bone resorption. Helodermin-like peptides may thus be capable of enhancing the direct effects of PTH on bone metabolism.