Species-divergent regulation of human and mouse osteocalcin genes by calciotropic hormones

Although osteocalcin is the most abundant noncollagenous protein in bone, i ts role remains undefined. Recent studies have reported diametrically oppos ing responses in the vitamin D regulation of the mouse vs the human and rat osteocalcin genes, The aim of this study was to increase the understanding of these differences and further elucidate the physiological function and regulation of osteocalcin. Direct comparison of the regulation of both the endogenous mouse osteocalcin gene (mOC) and a human osteocalcin promoter-ch loramphenicol acetyl transferase (hOC-CAT) reporter as integrated templates was undertaken in primary osteoblastic cultures from OSCAT transgenic mice . Expression of both genes was up-regulated with the onset of mineralizatio n, Long-term chronic 1,25-dihydroxyvitamin D-3 (1,25-(OH)(2)D-3) treatment and acute (2 day) PTH treatment inhibited both mOC and hOC-CAT expression. At all stages of osteoblastic development studied, hOC-CAT was up-regulated by acute 1,25-(OH)(2)D-3, whereas mOC was unaffected or inhibited. Mouse o steopontin was strongly up-regulated by acute 1,25-(OH)(2)D-3 treatment. Th us, the divergence of the osteocalcin responses to 1,25-(OH)(2)D-3 is speci fic for the osteocalcin gene and for an acute 1,25-(OH)(2)D-3 treatment reg ime. Elucidation of this unique aspect of bone physiology will provide valu able insights into the still incompletely understood roles of osteocalcin a nd 1,25-(OH)(2)D-3 in bone. (C) 2000 Academic Press.