BMP-2 vs. BMP-4 expression and activity in glucocorticoid-arrested MC3T3-E1 osteoblasts: Smad signaling, not alkaline phosphatase activity, predicts rescue of mineralization.

Luppen CA, Chandler RL, Noh T, Mortlock DP, Frenkel B
Growth Factors. 2008 26 (4): 226-37

PMID: 19021035 · PMCID: PMC3760374 · DOI:10.1080/08977190802277880

Pharmacological glucocorticoids (GCs) inhibit bone formation, leading to osteoporosis. GCs inhibit bone morphogenetic protein-2 (Bmp2) expression, and rhBMP-2 restores mineralization in GC-arrested osteoblast cultures. To better understand how GCs regulate BMPs, we investigated Bmp transcription, as well as rhBMP-induced Smad and alkaline phosphatase (ALP) activity. Bmp2 cis-regulatory regions were analyzed by reporter plasmids and LacZ-containing bacterial artificial chromosomes. We found that GCs inhibited Bmp2 via a domain > 50 kb downstream of the coding sequence. Bmp expression was evaluated by RT-PCR; whereas GCs strongly inhibited Bmp2, Bmp4 was abundantly expressed and resistant to GCs. Both rhBMP-2 and rhBMP-4 restored mineralization in GC-arrested cultures; rhBMP-2 was 5-fold more effective when dosing was based on ALP activation, however, the rhBMPs were equipotent when dosing was based on Smad transactivation. In conclusion, GCs regulate Bmp2 via a far-downstream domain, and activation of Smad, not ALP, best predicts the pro-mineralization potential of rhBMPs.

MeSH Terms (17)

3T3 Cells Alkaline Phosphatase Animals beta-Galactosidase Bone Morphogenetic Protein 2 Bone Morphogenetic Protein 4 Calcification, Physiologic Gene Expression Genes, Reporter Glucocorticoids Humans Luciferases Mice Osteoblasts Recombinant Proteins Signal Transduction Transfection

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