Osteoblast-Specific Transcription Factor Osterix Increases Vitamin D Receptor Gene Expression in Osteoblasts

被引:31
作者
Zhang, Chi [1 ,2 ,3 ]
Tang, Wanjin [1 ]
Li, Yang [1 ]
Yang, Fan [1 ]
Dowd, Diane R. [4 ]
MacDonald, Paul N. [4 ]
机构
[1] Univ Texas SW Med Ctr Dallas, Texas Scottish Rite Hosp Children, Bone Res Lab, Dallas, TX 75390 USA
[2] Univ Texas SW Med Ctr Dallas, Dept Orthoped Surg, Dallas, TX 75390 USA
[3] Univ Texas SW Med Ctr Dallas, Dept Pharmacol, Dallas, TX 75390 USA
[4] Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA
关键词
BONE-FORMATION; MEDIATED TRANSCRIPTION; DIFFERENTIATION; RICKETS; PROTEIN; CELLS; MICE; 1,25-DIHYDROXYVITAMIN-D; HOMEOSTASIS; ALOPECIA;
D O I
10.1371/journal.pone.0026504
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation from mesenchymal stem cells. In Osx knock-out mice, no bone formation occurs. The vitamin D receptor (VDR) is a member of the nuclear hormone receptor superfamily that regulates target gene transcription to ensure appropriate control of calcium homeostasis and bone development. Here, we provide several lines of evidence that show that the VDR gene is a target for transcriptional regulation by Osx in osteoblasts. For example, calvaria obtained from Osx-null embryos displayed dramatic reductions in VDR expression compared to wild-type calvaria. Stable overexpression of Osx stimulated VDR expression in C2C12 mesenchymal cells. Inhibition of Osx expression by siRNA led to downregulation of VDR. In contrast, Osx levels remained unchanged in osteoblasts in VDR-null mice. Mechanistic approaches using transient transfection assays showed that Osx directly activated a 1 kb fragment of the VDR promoter in a dose-dependent manner. To define the region of the VDR promoter that was responsive to Osx, a series of VDR promoter deletion mutants were examined and the minimal Osx-responsive region was refined to the proximal 120 bp of the VDR promoter. Additional point mutants were used to identify two GC-rich regions that were responsible for VDR promoter activation by Osx. Chromatin immunoprecipitation assays demonstrated that endogenous Osx was associated with the native VDR promoter in primary osteoblasts in vivo. Cumulatively, these data strongly support a direct regulatory role for Osx in VDR gene expression. They further provide new insight into potential mechanisms and pathways that Osx controls in osteoblasts and during the process of osteoblastic cell differentiation.
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页数:9
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共 29 条
[1]   Vitamin D action and regulation of bone remodeling: Suppression of osteoclastogenesis by the mature osteoblast [J].
Baldock, Paul A. ;
Thomas, Gethin P. ;
Hodge, Jason M. ;
Baker, Sara U. K. ;
Dressel, Uwe ;
O'Loughlin, Peter D. ;
Nicholson, Geoffrey C. ;
Briffa, Kathy H. ;
Eisman, John A. ;
Gardiner, Edith M. .
JOURNAL OF BONE AND MINERAL RESEARCH, 2006, 21 (10) :1618-1626
[2]   LONG-TERM NOCTURNAL CALCIUM INFUSIONS CAN CURE RICKETS AND PROMOTE NORMAL MINERALIZATION IN HEREDITARY RESISTANCE TO 1,25-DIHYDROXYVITAMIN-D [J].
BALSAN, S ;
GARABEDIAN, M ;
LARCHET, M ;
GORSKI, AM ;
COURNOT, G ;
TAU, C ;
BOURDEAU, A ;
SILVE, C ;
RICOUR, C .
JOURNAL OF CLINICAL INVESTIGATION, 1986, 77 (05) :1661-1667
[3]   Evidence for 1,25-dihydroxyvitamin D3-independent transactivation by the vitamin D receptor -: Uncoupling the receptor and ligand in keratinocytes [J].
Ellison, Tara I. ;
Eckert, Richard L. ;
MacDonald, Paul N. .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2007, 282 (15) :10953-10962
[4]   Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage [J].
Gardiner, EM ;
Baldock, PA ;
Thomas, GP ;
Sims, NA ;
Henderson, NK ;
Hollis, B ;
White, CP ;
Sunn, KL ;
Morrison, NA ;
Walsh, WR ;
Eisman, JA .
FASEB JOURNAL, 2000, 14 (13) :1908-1916
[5]   LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development [J].
Gong, YQ ;
Slee, RB ;
Fukai, N ;
Rawadi, G ;
Roman-Roman, S ;
Reginato, AM ;
Wang, HW ;
Cundy, T ;
Glorieux, FH ;
Lev, D ;
Zacharin, M ;
Oexle, K ;
Marcelino, J ;
Suwairi, W ;
Heeger, S ;
Sabatakos, G ;
Apte, S ;
Adkins, WN ;
Allgrove, J ;
Arslan-Kirchner, M ;
Batch, JA ;
Beighton, P ;
Black, GCM ;
Boles, RG ;
Boon, LM ;
Borrone, C ;
Brunner, HG ;
Carle, GF ;
Dallapiccola, B ;
De Paepe, A ;
Floege, B ;
Halfhide, ML ;
Hall, B ;
Hennekam, RC ;
Hirose, T ;
Jans, A ;
Jüppner, H ;
Kim, CA ;
Keppler-Noreuil, K ;
Kohlschuetter, A ;
LaCombe, D ;
Lambert, M ;
Lemyre, E ;
Letteboer, T ;
Peltonen, L ;
Ramesar, RS ;
Romanengo, M ;
Somer, H ;
Steichen-Gersdorf, E ;
Steinmann, B .
CELL, 2001, 107 (04) :513-523
[6]   Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. [J].
Horwood, NJ ;
Elliott, J ;
Martin, TJ ;
Gillespie, MT .
ENDOCRINOLOGY, 1998, 139 (11) :4743-4746
[7]   Cloning and characterization of the mouse vitamin D receptor promoter [J].
Jehan, F ;
DeLuca, HF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (19) :10138-10143
[8]   Activation of receptor activator of NF-κB ligand gene expression by 1,25-dihydroxyvitamin D3 is mediated through multiple long-range enhancers [J].
Kim, Sungtae ;
Yamazaki, Miwa ;
Zella, Lee A. ;
Shevde, Nirupama K. ;
Pike, J. Wesley .
MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (17) :6469-6486
[9]   Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts [J].
Komori, T ;
Yagi, H ;
Nomura, S ;
Yamaguchi, A ;
Sasaki, K ;
Deguchi, K ;
Shimizu, Y ;
Bronson, RT ;
Gao, YH ;
Inada, M ;
Sato, M ;
Okamoto, R ;
Kitamura, Y ;
Yoshiki, S ;
Kishimoto, T .
CELL, 1997, 89 (05) :755-764
[10]   Targeted ablation of the vitamin D receptor: An animal model of vitamin D-dependent rickets type II with alopecia [J].
Li, YC ;
Pirro, AE ;
Amling, M ;
Delling, G ;
Baroni, R ;
Bronson, R ;
DeMay, MB .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (18) :9831-9835