PARATHYROID-HORMONE REGULATES THE RAT COLLAGENASE-3 PROMOTER IN OSTEOBLASTIC CELLS THROUGH THE COOPERATIVE INTERACTION OF THE ACTIVATOR PROTEIN-1 SITE AND THE RUNT DOMAIN BINDING SEQUENCE

Parathyroid hormone induces collagenase-3 gene transcription in rat os teoblastic cells. Here, we characterized the basal, parathyroid hormon e regulatory regions of the rat collagenase-3 gene and the proteins in volved in this regulation. The minimal parathyroid hormone-responsive region was observed to be between base pairs -38 and -148, Deleted and mutated constructs showed that the activator protein-1 and the runt d omain binding sites are both required for basal expression and parathy roid hormone activation of this gene, The runt domain site is identica l to an osteoblast-specific element-2 or acute myelogenous leukemia bi nding sequence in the mouse and rat osteocalcin genes, respectively, O verexpression of an acute myelogenous leukemia-1 repressor protein inh ibited parathyroid hormone activation of the promoter, indicating a re quirement of acute myelogenous leukemia-related factor(s) for this act ivity. Overexpression of c-Fos, c-Jun, osteoblast-specific factor-2, a nd core binding factor-beta increased the response to parathyroid horm one of the wild type (-148) promoter but not with mutation of either o r both the activator protein-1 and runt domain binding sites. In summa ry, we conclude that there is a cooperative interaction of acute myelo genous leukemia/polyomavirus enhancer-binding protein-2-related factor (s) binding to the runt domain binding site with members of the activa tor protein-1 transcription factor family binding to the activator pro tein-1 site in the rat collagenase-3 gene in response to parathyroid h ormone in osteoblastic cells.