Identification of the homeobox protein Prx1 (MHox, Prrx-1) as a regulator of osterix expression and mediator of tumor necrosis factor α action in osteoblast differentiation.
Identification of the homeobox protein Prx1 (MHox, Prrx-1) as a regulator of osterix expression and mediator of tumor necrosis factor α action in osteoblast differentiation.
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DOI：
10.1002/jbmr.203
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发表时间：
2011-01
影响因子：
6.2
通讯作者：
Nanes, Mark S.
中科院分区：
文献类型：
--
作者：
Lu, Xianghuai;Beck, George R., Jr.;Gilbert, Linda C.;Camalier, Corinne E.;Bateman, Nicholas W.;Hood, Brian L.;Conrads, Thomas P.;Kern, Michael J.;You, Shaojin;Chen, Hong;Nanes, Mark S.
肿瘤坏死因子α（TNF-α）促进骨丢失并抑制骨形成。Osterix（Osx，SP 7）是成骨细胞（OB）分化所需的转录因子，因为缺失导致软骨骨架。我们以前描述了一个TNF抑制元件的Osx启动子，用于分离核蛋白介导的TNF抑制OB分化。将来自TNF处理的前OB的核提取物与TNF抑制元件一起孵育用于蛋白质下拉，并通过质谱法分析胰蛋白酶片段。染色质免疫沉淀（ChIP）测定证实了8个结合的转录因子。一种蛋白质，配对相关同源盒蛋白（Prx 1），以前已被证明在肢芽形成和骨骼模式中起关键作用。PCR显示Prx 1在原代基质细胞（MSCs）、C3 H10 T1/2细胞和MC 3 T3前成骨细胞中表达。TNF刺激Prx 1 mRNA增加14倍，MC 3 T3细胞中细胞快速积累，体内骨膜和小梁衬里细胞表达。Prx的瞬时表达抑制Osx和RUNX 2的转录。Prx 1b亚型或Prx 2的表达降低了前成骨细胞中Osx和RUNX 2的mRNA和OB分化。用siRNA沉默Prx 1可消除TNF对Osx mRNA的抑制，并增加基础Osx表达。电泳迁移率的变化显示Prx 1b作为首选的异构体结合的Osx启动子。这些结果确定同源异型盒蛋白Prx 1作为一个专性介质的TNF抑制Osx和分化的OB祖细胞。TNF激活Prx 1可能导致炎症性关节炎、绝经和衰老中骨形成减少。© 2011美国骨与矿物质研究学会。
Tumor necrosis factor α (TNF-α) promotes bone loss and inhibits bone formation. Osterix (Osx, SP7) is a transcription factor required for osteoblast (OB) differentiation because deletion results in a cartilaginous skeleton. We previously described a TNF suppressor element in the Osx promoter that was used to isolate nuclear proteins mediating TNF inhibition of OB differentiation. Nuclear extracts from TNF-treated pre-OBs were incubated with the TNF suppressor element for protein pull-down, and tryptic fragments were analyzed by mass spectrometry. Chromatin immunoprecipitation (ChIP) assay confirmed eight bound transcription factors. One protein, the paired related homeobox protein (Prx1), had been shown previously to have a critical role in limb bud formation and skeletal patterning. PCR revealed Prx1 expression in primary stromal cells (MSCs), C3H10T1/2 cells, and MC3T3 preosteoblasts. TNF stimulated a 14-fold increase in mRNA for Prx1, rapid cell accumulation in MC3T3 cells, and expression in periosteal and trabecular lining cells in vivo. Transient expression of Prx inhibited transcription of Osx and RUNX2. Expression of the Prx1b isoform or Prx2 decreased Osx and RUNX2 mRNA and OB differentiation in preosteoblasts. Silencing of Prx1 with siRNA abrogated TNF suppression of Osx mRNA and increased basal Osx expression. Electrophoretic mobility shift revealed Prx1b as the preferred isoform binding the Osx promoter. These results identify the homeobox protein Prx1 as an obligate mediator of TNF inhibition of Osx and differentiation of OB progenitors. Activation of Prx1 by TNF may contribute to reduced bone formation in inflammatory arthritis, menopause, and aging. © 2011 American Society for Bone and Mineral Research.
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影响因子：
4.8
作者：
Gilbert, L;He, XF;Nanes, MS
通讯作者：
Nanes, MS
DOI：
10.1007/s00281-003-0125-3
发表时间：
2003-08-01
期刊：
SPRINGER SEMINARS IN IMMUNOPATHOLOGY
影响因子：
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作者：
Li, P;Schwarz, EM
通讯作者：
Schwarz, EM
影响因子：
4.8
作者：
Gilbert, L;He, XF;Nanes, MS
通讯作者：
Nanes, MS
影响因子：
2.5
作者：
Chesterman, ES;Gainey, GD;Kern, MJ
通讯作者：
Kern, MJ
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影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G