Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
Lead induces chondrogenesis and alters transforming growth factor-beta and bone morphogenetic protein signaling in mesenchymal cell populations.
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DOI：
10.1289/ehp.10028
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发表时间：
2007-09
影响因子：
10.4
通讯作者：
O'Keefe RJ
中科院分区：
文献类型：
--
作者：
Zuscik MJ;Ma L;Buckley T;Puzas JE;Drissi H;Schwarz EM;O'Keefe RJ
已经确定，接触铅的儿童骨骼生长受到阻碍。由于软骨形成是骨骼发育过程中的一个开创性步骤，因此阐明铅对这一过程的影响是了解铅在骨骼中毒性机制的第一步。本研究的目的是测试的假设，铅改变间充质细胞的软骨形成的承诺，并评估铅对各种信号通路的影响。我们评估了铅对软骨形成的影响，在小鼠肢芽间充质细胞（MSCs）结节形成试验和基因分析。采用基于双链酶的报告基因和Western分析研究了铅对转化生长因子-β（TGF-β）和骨形态发生蛋白（BMP）信号传导的影响，并采用基于双链酶的分析研究了环磷酸腺苷反应元件结合蛋白（CREB）、β-连环蛋白、AP-1和核因子-κ B（NF-κB）信号传导。我们还使用了异位骨形成试验，以确定如何铅影响体内软骨形成。Pb暴露的MSC显示出增强的软骨形成的基础和TGF-β/BMP诱导，通过增强的结节形成和Sox-9、2型胶原和聚集蛋白聚糖（所有软骨形成的关键标志物）的上调来证明。我们观察到增强软骨形成过程中异位骨形成的小鼠通过饮用水预先暴露于铅。在MSC中，Pb增强TGF-β但抑制BMP-2信号传导，如通过荧光素酶报告基因测定和Smad磷酸化的Western分析所测量的。虽然铅对基础CREB或Wnt/β-catenin通路活性没有影响，但它诱导NFκB信号传导并抑制AP-1信号传导。铅在体内外诱导软骨形成可能涉及多种信号通路的调节和整合，包括TGF-β、BMP、AP-1和NFκB。
It has been established that skeletal growth is stunted in lead-exposed children. Because chondrogenesis is a seminal step during skeletal development, elucidating the impact of Pb on this process is the first step toward understanding the mechanism of Pb toxicity in the skeleton. The aim of this study was to test the hypothesis that Pb alters chondrogenic commitment of mesenchymal cells and to assess the effects of Pb on various signaling pathways. We assessed the influence of Pb on chondrogenesis in murine limb bud mesenchymal cells (MSCs) using nodule formation assays and gene analyses. The effects of Pb on transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling was studied using luciferase-based reporters and Western analyses, and luciferase-based assays were used to study cyclic adenosine monophosphate response element binding protein (CREB), β-catenin, AP-1, and nuclear factor-kappa B (NF-κB) signaling. We also used an ectopic bone formation assay to determine how Pb affects chondrogenesis in vivo. Pb-exposed MSCs showed enhanced basal and TGF-β/BMP induction of chondrogenesis, evidenced by enhanced nodule formation and up-regulation of Sox-9, type 2 collagen, and aggrecan, all key markers of chondrogenesis. We observed enhanced chondrogenesis during ectopic bone formation in mice preexposed to Pb via drinking water. In MSCs, Pb enhanced TGF-β but inhibited BMP-2 signaling, as measured by luciferase reporter assays and Western analyses of Smad phosphorylation. Although Pb had no effect on basal CREB or Wnt/β-catenin pathway activity, it induced NFκB signaling and inhibited AP-1 signaling. The in vitro and in vivo induction of chondrogenesis by Pb likely involves modulation and integration of multiple signaling pathways including TGF-β, BMP, AP-1, and NFκB.
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影响因子：
2.8
作者：
Grimsrud, CD;Romano, PR;O'Keefe, RJ
通讯作者：
O'Keefe, RJ
影响因子：
3.5
作者：
Hwang, SG;Yu, SS;Chun, JS
通讯作者：
Chun, JS
DOI：
10.1016/0922-3371(88)90056-1
发表时间：
1988-09-01
期刊：
CELL DIFFERENTIATION AND DEVELOPMENT
影响因子：
--
作者：
BIDDULPH, DM;DOZIER, MM;SAWYER, LM
通讯作者：
SAWYER, LM
影响因子：
11.8
作者：
Day, TF;Guo, XZ;Yang, YZ
通讯作者：
Yang, YZ
影响因子：
3.1
作者：
AHRENS, M;ANKENBAUER, T;GROSS, G
通讯作者：
GROSS, G