BMP-2 and TGF-beta stimulate expression of beta1,3-glucuronosyl transferase 1 (GlcAT-1) in nucleus pulposus cells through AP1, TonEBP, and Sp1: role of MAPKs.
BMP-2 and TGF-beta stimulate expression of beta1,3-glucuronosyl transferase 1 (GlcAT-1) in nucleus pulposus cells through AP1, TonEBP, and Sp1: role of MAPKs.
复制标题
DOI：
10.1359/jbmr.091202
复制
发表时间：
2010-05
期刊：
影响因子：
--
通讯作者：
Risbud MV
中科院分区：
文献类型：
--
作者：
Hiyama A;Gogate SS;Gajghate S;Mochida J;Shapiro IM;Risbud MV
本研究的目的是探讨骨形态发生蛋白2 （BMP-2）和转化生长因子β (TGF-β)对髓核细胞中硫酸软骨素合成的重要调节因子β1,3-葡萄糖醛基转移酶1 （GlcAT-1）表达的控制。两种生长因子均可诱导GlcAT-1表达和启动子活性。缺失分析表明，缺乏AP1和TonE位点的启动子结构对生长因子处理无反应。利用显性阴性蛋白进行的实验表明，这些转录因子和Sp1是诱导GlcAT-1启动子活性所必需的。此外，当AP1或TonE结合位点突变时，诱导被抑制。BMP-2和TGF-β均增加c-Jun和TonEBP的表达和磷酸化。我们研究了生长因子治疗后丝裂原活化蛋白激酶（MAPK）信号通路的作用；发现ERK1/2、p38和JNK的瞬时激活。用MAPK抑制剂治疗可阻断BMP-2-和TGF-β-诱导的AP1报告功能、GlcAT-1表达和GAG积累。我们发现DN-ERK1而不是DN-ERK2导致生长因子介导的GlcAT-1启动子活性的抑制；我们还发现p38δ在GlcAT-1激活中很重要。这些研究结果表明，BMP-2和TGF-β通过MAPK、AP1、Sp1和TonEBP组成的信号网络调节髓核细胞中GlcAT-1的表达。综上所述，这些生长因子通过控制GAG和聚集蛋白的合成，对盘细胞功能产生积极影响。©2010美国骨与矿物研究学会。
The goal of the study was to investigate bone morphogenetic protein 2 (BMP-2) and transforming growth factor β (TGF-β) control of the expression of β1,3-glucuronosyl transferase 1 (GlcAT-1), an important regulator of chondroitin sulfate synthesis in cells of the nucleus pulposus. Treatment with both growth factors resulted in induction of GlcAT-1 expression and promoter activity. Deletion analysis indicated that promoter constructs lacking AP1 and TonE sites were unresponsive to growth factor treatment. Experiments using dominant-negative proteins showed that these transcription factors along with Sp1 were required for induction of GlcAT-1 promoter activity. Moreover, when either AP1 or TonE binding sites were mutated, induction was suppressed. Both BMP-2 and TGF-β increased c-Jun and TonEBP expression and phosphorylation of transactivation domains. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway following growth factor treatment; a robust and transient activation of ERK1/2, p38, and JNK was noted. Treatment with MAPK inhibitors blocked BMP-2- and TGF-β-induced AP1 reporter function, GlcAT-1 expression, and GAG accumulation. We found that DN-ERK1 but not DN-ERK2 resulted in suppression of growth factor–mediated induction of GlcAT-1 promoter activity; we also showed that p38δ was important in GlcAT-1 activation. Results of these studies demonstrate that BMP-2 and TGF-β regulate GlcAT-1 expression in nucleus pulposus cells through a signaling network comprising MAPK, AP1, Sp1, and TonEBP. It is concluded that by controlling both GAG and aggrecan synthesis, these growth factors positively influence disk cell function. © 2010 American Society for Bone and Mineral Research.
登录
查看更多内容
影响因子：
4.8
作者：
Tsai, Tsung-Ting;Danielson, Keith G.;Risbud, Makarand V.
通讯作者：
Risbud, Makarand V.
影响因子：
2.5
作者：
Choi, Kyung-Suk;Cohn, Martin J.;Harfe, Brian D.
通讯作者：
Harfe, Brian D.
影响因子：
4.8
作者：
Lam, AKM;Ko, BCB;Chung, SSM
通讯作者：
Chung, SSM
影响因子：
4
作者：
Nesti, Leon J.;Caterson, E. J.;Tuan, Rocky S.
通讯作者：
Tuan, Rocky S.
影响因子：
2.9
作者：
Robinson, MJ;Harkins, PC;Goldsmith, EJ
通讯作者：
Goldsmith, EJ