Bone morphogenetic proteins induce gremlin, a protein that limits their activity in osteoblasts

Bone morphogenetic proteins (BMP) induce the differentiation of cells of th e osteoblastic lineage and enhance the function of the osteoblast. Growth f actor activity is regulated by binding proteins, and we previously showed t hat BMPs induce noggin, a glycoprotein that binds and blocks BMP action. Re cently, additional BMP antagonists, such as gremlin, have been described, b ut there is no information about their expression or function in osteoblast s. We tested for the expression of gremlin and studied its induction by BMP s in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvar iae (Ob cells). BMP-2 caused a time- and dose-dependent increase in gremlin messenger RNA and polypeptide levels, as determined by Northern and Wester n blot analyses. The effects of BMP-2 on gremlin transcripts were independe nt of new protein synthesis. BMP-2 increased the rate of gremlin transcript ion as determined by nuclear run-on assays. Fibroblast growth factor-a and platelet-derived growth factor BE also induced gremlin, but other hormones and growth factors had no effect. Gremlin prevented the stimulatory effects of BMP-2 on DNA, collagen, noncollagen protein synthesis, and alkaline pho sphatase activity in Ob cells. In conclusion, BMPs induce gremlin transcrip tion in Ob cells, a mechanism that probably limits BMP action in osteoblast s.