An Enhancer 20 Kilobases Upstream of the Human Receptor Activator of Nuclear Factor-κB Ligand Gene Mediates Dominant Activation by 1,25-Dihydroxyvitamin D3

Objectives. To study effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on RANKL signaling pathway and pathway-associated cytokines in patients with rheumatoid arthritis (RA).Methods. Receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), IFN-γ, IL-6, TNF-α, IL-17, and IL-4 were examined in 54 patients with incipient RA using a cytometric bead array (CBA) or an enzyme-linked immunosorbent assay (ELISA).Results. After 72 hours of incubation of peripheral blood mononuclear cells (PBMCs) with 1,25(OH)2D3in RA patients, the levels of RANKL, TNF-α, IL-17 and IL-6 significantly decreased compared to those of the control. 1,25(OH)2D3had no significantly impact on the levels of OPG, RANKL/OPG, and IL-4.Conclusions. The present study demonstrated that 1,25(OH)2D3reduced the production of RANKL and the secretion of TNF-α, IL-17, and IL-6 in PBMCs of RA patients, which indicated that 1,25(OH)2D3might be able to decrease damage of cartilage and bone in RA patients by regulating the expression of RANKL signaling pathway and pathway-associated cytokines.

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1,25-Dihydroxyvitamin D3 suppresses inflammation-induced expression of plasminogen activator inhibitor-1 by blocking nuclear factor-κB activation

Archives of Biochemistry and Biophysics ◽

10.1016/j.abb.2010.12.020 ◽

2011 ◽

Vol 507 (2) ◽

pp. 241-247 ◽

Cited By ~ 58

Author(s):

Yunzi Chen ◽

Juan Kong ◽

Tao Sun ◽

George Li ◽

Frances L. Szeto ◽

...

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Plasminogen Activator Inhibitor 1 ◽

Induced Expression ◽

Dihydroxyvitamin D3 ◽

1,25 Dihydroxyvitamin D3 ◽

Activator Inhibitor

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Targeted Deletion of a Distant Transcriptional Enhancer of the Receptor Activator of Nuclear Factor-κB Ligand Gene Reduces Bone Remodeling and Increases Bone Mass

Endocrinology ◽

10.1210/en.2007-0734 ◽

2007 ◽

Vol 149 (1) ◽

pp. 146-153 ◽

Cited By ~ 75

Author(s):

Carlo Galli ◽

Lee A. Zella ◽

Jackie A. Fretz ◽

Qiang Fu ◽

J. Wesley Pike ◽

...

Keyword(s):

Bone Mass ◽

Bone Remodeling ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Rankl Expression ◽

Transcriptional Enhancer ◽

Dihydroxyvitamin D3 ◽

Rankl Mrna ◽

Receptor Activator ◽

Stimulation Of

Receptor activator of nuclear factor-κB ligand (RANKL) is essential for osteoclast differentiation, and hormones and cytokines that stimulate bone resorption increase RANKL expression in stromal/osteoblastic cells. We have previously shown that PTH and 1,25-dihydroxyvitamin D3 control murine RANKL gene expression in vitro, in part, via an evolutionarily conserved transcriptional enhancer, designated the distal control region (DCR), located 76 kb upstream from the transcription start site. Herein we describe the phenotype of mice lacking this enhancer. Deletion of the DCR reduced PTH and 1,25-dihydroxyvitamin D3 stimulation of RANKL mRNA and osteoclast formation in primary bone marrow cultures as well as stimulation of RANKL mRNA in bone. DCR deletion also reduced basal RANKL mRNA levels in bone, thymus, and spleen. Moreover, mice lacking the DCR exhibited increased bone mass and strength. The increase in bone mass was due to reduced osteoclast and osteoblast formation leading to a low rate of bone remodeling similar to that observed in humans and mice with hypoparathyroidism. These findings demonstrate that hormonal control of RANKL expression via the DCR is a critical determinant of the rate of bone remodeling.

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