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Papers In Press, published online ahead of print July 12, 2001
J. Biol. Chem, 10.1074/jbc.M104319200
Submitted on May 11, 2001
Revised on July 12, 2001
Accepted on July 12, 2001
Gene Regulation, Bone and Inflammation Research, Eli Lilly and Company, Indianapolis, IN 46258
Corresponding Author: jeo{at}lilly.com
Transforming growth factor-¦Â (TGF-¦Â ) regulates osteoclastogenesis and osteoclast survival, in part through the induction of osteoprotegerin (OPG), a protein known to inhibit osteoclast formation and function. To explore the molecular basis of TGF-¦Â regulation of OPG expression, we evaluated the effects of TGF-¦Â on osteoclast formation, OPG protein secretion, mRNA expression and gene transcription. The marked inhibitory effect of TGF-¦Â on osteoclast differentiation was confirmed in a co-culture model utilizing murine stromal/osteoblastic BALC cells and bone marrow hematopoietic precursors. This inhibition in osteoclast differentiation was preceded by a decrease in RANKL mRNA expression (5-fold) and a reciprocal increase in OPG mRNA (6.1-fold) and protein (7.1-fold) expression in BALC cells. At the promoter/transcriptional level, TGF-¦Â treatment resulted in a 3- to 10-fold increase in reporter gene activity directed by a 5.9-kb fragment of the human OPG promoter in transfection assays performed in UMR106 cells. The effect of TGF-¦Â was mimicked by TGF-¦Â 2 and -“´¬–”²ª› 3, but not BMP-4,suggesting a TGF-¦Â signal-specific effect. Deletion analysis revealed that a 183-bp region (?372 to ?190) in the promoter was required for TGF-¦Â responsiveness, and this region was sufficient to confer TGF-¦Â inducibility to a heterologous (osteocalcin) minimal promoter. Substitution mutations that disrupted the Cbfa1- and/or Smad- binding elements present in the 183-bp region resulted in a decrease in baseline expression and in the responsiveness to TGF-¦Â and Cbfa1. Collectively, these studies indicate the involvement and possible interaction of Cbfa1 and Smad proteins in mediating the effects of TGF-¦Â on OPG transcription.
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