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Modulation of mouse RANKL gene expression by Runx2 and vitamin D 3
Author(s) -
Kitazawa Riko,
Mori Kiyoshi,
Yamaguchi Akira,
Kondo Takeshi,
Kitazawa Sohei
Publication year - 2008
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.21929
Subject(s) - rankl , runx2 , activator (genetics) , gene expression , chemistry , microbiology and biotechnology , transfection , receptor , regulation of gene expression , biology , endocrinology , medicine , gene , biochemistry
The expression of receptor activator of nuclear factor‐κB ligand (RANKL) is regulated by bone‐seeking hormones such as PTH and 1α,25‐dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ). Runx2, a master gene for osteoblastic differentiation, also modulates osteoclastogenesis by regulating the RANKL gene. To elucidate the mechanism whereby runx2 and 1,25(OH) 2 D 3 regulate RANKL expression, we studied the function of runx2 on the chromatin structure and on the proximal binding sites using osteoblastic cell lines derived from normal (ST2) and runx2‐deficient mice (RD‐C6). Although the expression of RANKL in the steady‐state was higher in RD‐C6 than in ST2, 1,25(OH) 2 D 3 ‐treatment of the cells increased it 20‐fold in ST2 but only 1.8‐fold in RD‐C6. Transient transfection studies with proximal RANKL 2kb promoter, runx2 knock‐down in ST2, and forced expression of runx2 in RD‐C6 all confirmed that runx2 set the steady‐state expression of the RANKL gene at a low level, but exerted a positive effect on enhanced transcriptional activity in response to 1,25(OH) 2 D 3 . Also, assessment of the acetylation status of the area spanning 40 kb upstream of the basic promoter in ST2 and RD‐C6 by ChIP assay revealed that whereas H3 and H4 histone acetylation was detected even in the steady‐state in RD‐C6, it was detected only with 1,25(OH) 2 D 3 in ST2. In the steady‐state, runx2 may suppress RANKL gene by condensing the chromatin structure; however, it exerts a positive effect on 1,25(OH) 2 D 3 ‐induced RANKL transcription when the proximal runx2 sites are accessible. Thus, RANKL expression in stromal/osteoblastic cells is keenly regulated by 1,25(OH) 2 D 3 which transactivates the gene at two different levels. J. Cell. Biochem. 105: 1289–1297, 2008. © 2008 Wiley‐Liss, Inc.

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