LMP-1, A LIM-DOMAIN PROTEIN, MEDIATES BMP-6 EFFECTS ON BONE-FORMATION

Glucocorticoids can promote osteoblast differentiation from fetal calv arial cells and bone marrow stromal cells. We recently reported that g lucocorticoid specifically induced bone morphogenetic protein-6 (BMP-6 ), a glycoprotein signaling molecule that is a multifunctional regulat or of vertebrate development. In the present study, we used fetal rat secondary calvarial cultures to determine genes induced during early o steoblast differentiation as initiated by glucocorticoid treatment. Gl ucocorticoid, and subsequently BMP-6, was found to induce a novel rat intracellular protein, LIM mineralization protein-1 (LMP-1), that in t urn resulted in synthesis of one or more soluble factors that could in duce de novo bone formation. Blocking expression of LMP-1 using antise nse oligonucleotide prevented osteoblast differentiation in vitro. Ove rexpression of LMP-1 using a mammalian expression vector was sufficien t to initiate de novo bone nodule formation in vitro and in sc implant s in vivo. These data demonstrate that LMP-1 is an essential positive regulator of the osteoblast differentiation program as well as an impo rtant intermediate step in the BMP-6 signaling pathway.