Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5
Retinoic acid stimulates chondrocyte differentiation and enhances bone morphogenetic protein effects through induction of Smad1 and Smad5
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DOI：
10.1210/en.2002-220969
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发表时间：
2003-06-01
期刊：
影响因子：
4.8
通讯作者：
O'Keefe, RJ
中科院分区：
文献类型：
--
作者：
Li, XF;Schwarz, EM;O'Keefe, RJ
而骨形态发生蛋白（BMP）信号事件诱导成熟的特点，在体外，最近的证据表明，其他监管机构的影响可能是通过BMP信号事件介导的。本研究探讨了维甲酸（RA）刺激鸡胚胸骨软骨细胞分化的机制。RA和BMP-2诱导软骨细胞成熟标志物colX在软骨细胞培养物中表达8天。虽然RA的影响很小，但它协同增强了BMP-2对colX和磷酸酶活性的影响。用选择性抑制剂抑制RA或BMP信号传导，干扰了这些药剂的诱导作用，但也抑制了互补途径，证明了在软骨细胞成熟过程中RA和BMP信号传导的相互依赖性。BMP-2没有增强RA对RA反应性报告构建体的作用，但RA增强了基础活性，并协同增强了BMP-2对BMP反应性鸡X型胶原报告体的刺激。在colX表达上观察到RA和BMP-2之间的类似协同相互作用。RA没有增加IA型BMP受体的表达，但显著上调Smad 1和Smad 5蛋白的表达，这是BMP通路的重要参与者。用选择性抑制剂AGN 193109抑制RA信号传导，阻断了RA介导的Smad蛋白和软骨细胞分化的诱导。这些发现表明，RA诱导BMP信号分子的表达，并增强软骨细胞中BMP的作用。
Whereas bone morphogenetic protein (BMP)-signaling events induce maturational characteristics in vitro, recent evidence suggests that the effects of other regulators might be mediated through BMP-signaling events. The present study examines the mechanism through which retinoic acid (RA) stimulates differentiation in chicken embryonic caudal sternal chondrocyte cultures. Both RA and BMP-2 induced expression of the chondrocyte maturational marker, colX, in chondrocyte cultures by 8 d. Though the RA effect was small, it synergistically enhanced the effect of BMP-2 on colX and phosphatase activity. Inhibition of either RA or BMP signaling, with selective inhibitors, interfered with the inductive effects of these agents but also inhibited the complementary pathway, demonstrating a codependence of RA and BMP signaling during chondrocyte maturation. BMP-2 did not enhance the effects of RA on an RA-responsive reporter construct, but RA enhanced basal activity and synergistically enhanced BMP-2 stimulation of the BMP-responsive chicken type X collagen reporter. A similar synergistic interaction between RA and BMP-2 was observed on colX expression. RA did not increase the expression of the type IA BMP receptor but did markedly up-regulate the expression of Smad1 and Smad5 proteins, important participants in the BMP pathway. Inhibition of RA signaling, with the selective inhibitor AGN 193109, blocked RA-mediated induction of the Smad proteins and chondrocyte differentiation. These findings demonstrate that RA induces the expression of BMP-signaling molecules and enhances BMP effects in chondrocytes.