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Endocrinology Vol. 141, No. 12 4558-4563
Copyright © 2000 by The Endocrine Society

ARTICLES

Bone Morphogenetic Proteins Induce Gremlin, a Protein That Limits Their Activity in Osteoblasts1

Renata C. Pereira, Aris N. Economides and Ernesto Canalis

Departments of Research (R.C.P., E.C.) and Medicine (E.C.) , Saint Francis Hospital and Medical Center, Hartford, Connecticut 06105; University of Connecticut School of Medicine (E.C.), Farmington, Connecticut 06030; and Regeneron Pharmaceuticals, Inc. (A.N.E.), Tarrytown, New York 10591

Address all correspondence and requests for reprints to: Ernesto Canalis, M.D., Department of Research, Saint Francis Hospital and Medical Center, 114 Woodland Street, Hartford, Connecticut 06105-1299. E-mail: ecanalis{at}stfranciscare.org

Bone morphogenetic proteins (BMP) induce the differentiation of cells of the osteoblastic lineage and enhance the function of the osteoblast. Growth factor activity is regulated by binding proteins, and we previously showed that BMPs induce noggin, a glycoprotein that binds and blocks BMP action. Recently, additional BMP antagonists, such as gremlin, have been described, but there is no information about their expression or function in osteoblasts. We tested for the expression of gremlin and studied its induction by BMPs in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvariae (Ob cells). BMP-2 caused a time- and dose-dependent increase in gremlin messenger RNA and polypeptide levels, as determined by Northern and Western blot analyses. The effects of BMP-2 on gremlin transcripts were independent of new protein synthesis. BMP-2 increased the rate of gremlin transcription as determined by nuclear run-on assays. Fibroblast growth factor-2 and platelet-derived growth factor BB 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 phosphatase activity in Ob cells. In conclusion, BMPs induce gremlin transcription in Ob cells, a mechanism that probably limits BMP action in osteoblasts.




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