It is well known that the expression of osteocalcin, the only recognized osteoblast-specific protein, is regulated by 1 alpha-25-dihydroxyvitamin D3 through a distinct vitamin D3 receptor and a cis-acting DNA response element. In addition, recent data obtained with plasmid constructs have shown a positive interaction between retinoic acid activated receptor(s) and the osteocalcin gene promoter. Our studies, carried out on primary cultures of human osteoblasts, have demonstrated for the first time the activation of the osteocalcin gene expression by retinoic acid. Moreover, a remarkable synergistic effect between the hormonal forms of vitamin A and D3 on the synthesis of this bone-specific protein was observed.