Runx2 integrates estrogen activity in osteoblasts.
Steroids significantly effect skeletal integrity. For example, bone mass decreases with glucocorticoid excess or with estrogen depletion after menopause. Glucocorticoid suppresses gene expression by an essential skeletal tissue transcription factor, Runx2, in rat osteoblasts. We now report that estrogen enhances Runx2 activity in dose- and estrogen receptor-dependent ways independently of changes in Runx2 levels or its DNA binding potential. Estrogen receptor and Runx2 can be collected by co-immunoprecipitation. By two-hybrid gene expression analysis, high affinity complex formation involves portions of Runx2 outside of its own DNA binding domain and the DNA binding domain of the estrogen receptor. Consistent with this interaction, the stimulatory effect of estrogen on Runx2 activity is lost when the DNA binding domain of the estrogen receptor is eliminated. Unlike the stimulatory effect of estrogen and the inhibitory effect of glucocorticoid, androgen fails to increase Runx2 activity, whereas Runx2 potently suppresses gene expression induced by all three steroids. Finally, estrogen increases gene transcription by the transforming growth factor-beta type I receptor gene promoter, which contains several Runx binding sequences, and enhances Smad dependent gene expression by transforming growth factor-beta in osteoblasts. These results reveal that Runx2 can integrate complex effects on gene transcription in hormone-, growth factor-, and tissue-restricted ways.
McCarthy
Thomas L
TL
Department of Surgery, Yale University School of Medicine, New Haven, Connecticut 06520-8041, USA. tomas.mccarthy@yale.edu
Chang
Wei-Zhong
WZ
Liu
Yuan
Y
Centrella
Michael
M
D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha; D004967:Estrogens / Q000378:metabolism*; D005938:Glucocorticoids / Q000378:metabolism; D008954:Models, Biological; D009363:Neoplasm Proteins; D010006:Osteoblasts / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D047628:Estrogen Receptor alpha; D004967:Estrogens; D005938:Glucocorticoids; D009363:Neoplasm Proteins; D011960:Receptors, Estrogen; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D004247:DNA; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone