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Endocrinology, Vol 134, 2524-2531, Copyright © 1994 by Endocrine Society
ARTICLES |
H Kuno, SM Kurian, GN Hendy, J White, HF deLuca, CO Evans and MS Nanes
Division of Endocrinology and Metabolism, Emory University School of Medicine, Atlanta, Georgia 30033.
Control of osteoblast function requires the coordinate activity of systemic and local regulatory factors. We have investigated the mechanism of interaction between the secosteroid 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and the cytokine tumor necrosis factor-alpha (TNF- alpha) by measuring their effects on two 1,25-(OH)2D3 responsive matrix protein genes, osteocalcin (OC) and osteopontin (OP). Our previous studies revealed that an inhibitory effect of TNF-alpha on 1,25-(OH)2D3- stimulated OC gene transcription is conferred by the same 25 base pair region of 5'-flanking DNA that confers a response to vitamin D (VDRE). Gel mobility shift studies of [32P]VDRE binding to ROS 17/2.8 cell nuclear extract revealed that TNF-alpha inhibits 1,25-(OH)2D3 stimulated formation of specific retinoid X receptor/vitamin D receptor (RXR/VDR)-DNA complexes in vitro. To determine if TNF-alpha was inhibiting nuclear protein-VDRE binding by modulation of VDR availability, we measured intranuclear VDR in cells treated with 1,25- (OH)2D3 (10(-8) M), TNF-alpha (100 ng/ml), or both, by western blot. 1,25-(OH)2D3 caused upregulation of the nuclear VDR. Treatment with TNF- alpha inhibited the 1,25-(OH)2D3-stimulated up-regulation of VDR nuclear protein content. However, down-regulation of VDR was unlikely to be the mechanism of TNF-alpha action because TNF-alpha had no effect on 1,25-(OH)2D3 stimulation of steady state OP messenger RNA or transcription of an OP-VDRE-chloramphenicol acetyl transferase reporter construct. These results suggest that decreased VDR alone does not explain the mechanism of TNF-alpha action. VDRE structural requirements for TNF-alpha action were characterized by comparing binding of mutant and hybrid forms of mouse (m)OP-, rat (r)OC-, and human (h)OC-VDRE probes to nuclear protein from cells treated with 1,25-(OH)2D3 and/or TNF-alpha. These homologous vitamin D response elements differ in that an AP-1 sequence is included in the rOC-VDRE and hOC-VDRE but not in the OP-VDRE. Gel mobility shift analysis revealed that TNF-alpha inhibited 1,25-(OH)2D3 stimulation of nuclear protein binding to rOC- VDRE and hOC-VDRE to 59% and 69% of control, respectively, but had no effect on 1,25-(OH)2D3 stimulation of nuclear protein binding to OP- VDRE. The effect of TNF-alpha could not be conferred in a mutant OP- VDRE in which the rOC-VDRE AP-1 sequence was inserted.(ABSTRACT TRUNCATED AT 400 WORDS)
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