BMP-2 and TGF-β1 mediate biglycan-induced pro-osteogenic reprogramming in aortic valve interstitial cells.
BMP-2 and TGF-β1 mediate biglycan-induced pro-osteogenic reprogramming in aortic valve interstitial cells.
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DOI：
10.1007/s00109-014-1229-z
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发表时间：
2015-04
影响因子：
4.7
通讯作者：
Meng, Xianzhong
中科院分区：
文献类型：
--
作者：
Song, Rui;Fullerton, David A.;Ao, Lihua;Zheng, Daniel;Zhao, Ke-seng;Meng, Xianzhong
双糖蛋白聚糖在钙化性主动脉瓣疾病（CAVD）影响的主动脉瓣中积累，可溶性双糖蛋白聚糖通过Toll样受体（TLR）2上调人主动脉瓣间质细胞（AVIC）中BMP-2的表达，并诱导AVIC促成骨重编程，其特征在于升高的促成骨活性。我们试图确定在人类AVIC中负责双糖链聚糖诱导的促成骨重编程的因素。用重组双糖蛋白聚糖处理AVIC诱导BMP-2和TGF-β1的分泌，但不诱导BMP-4或BMP-7的分泌。Biglycan以TLR 4依赖的方式上调TGF-β1的表达。BMP-2或TGF-β1的中和作用减弱了暴露于双糖链蛋白聚糖的细胞中ALP、骨桥蛋白和Runx 2的表达。然而，BMP-2和TGF-β1的中和作用消除了这些成骨生物标志物的表达和钙沉积。在暴露于双糖链蛋白聚糖的细胞中检测到磷酸化的Smad 1和Smad 3，并且Smad 1或Smad 3的敲低减弱了双糖链蛋白聚糖对成骨生物标志物表达的影响。虽然BMP-2和TGF-β1各自上调成骨生物标志物的表达，但暴露于BMP-2加TGF-β1诱导更大的上调并导致钙沉积。我们的结论是，BMP-2和TGF-β1的同时上调是负责双糖蛋白诱导的人AVIC中的前成骨重编程。Smad 1/3通路参与AVIC促成骨重编程的机制。
Biglycan accumulates in aortic valves affected by calcific aortic valve disease (CAVD), and soluble biglycan up-regulates BMP-2 expression in human aortic valve interstitial cells (AVICs) via Toll-like receptor (TLR) 2 and induces AVIC pro-osteogenic reprogramming, characterized by elevated pro-osteogenic activities. We sought to identify the factors responsible for biglycan-induced pro-osteogenic reprogramming in human AVICs. Treatment of AVICs with recombinant biglycan induced the secretion of BMP-2 and TGF-β1, but not BMP-4 or BMP-7. Biglycan up-regulated TGF-β1 expression in a TLR4-dependent fashion. Neutralization of BMP-2 or TGF-β1 attenuated the expression of ALP, osteopontin and Runx2 in cells exposed to biglycan. However, neutralization of both BMP-2 and TGF-β1 abolished the expression of these osteogenic biomarkers and calcium deposition. Phosphorylated Smad1 and Smad3 were detected in cells exposed to biglycan, and knockdown of Smad1 or Smad3 attenuated the effect of biglycan on the expression of osteogenic biomarkers. While BMP-2 and TGF-β1 each up-regulated the expression of osteogenic biomarkers, an exposure to BMP-2 plus TGF-β1 induced a greater up-regulation and results in calcium deposition. We conclude that concurrent up-regulation of BMP-2 and TGF-β1 is responsible for biglycan-induced pro-osteogenic reprogramming in human AVICs. The Smad 1/3 pathways are involved in the mechanism of AVIC pro-osteogenic reprogramming.
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影响因子：
5.3
作者：
Kaden, JJ;Dempfle, CE;Borggrefe, M
通讯作者：
Borggrefe, M
影响因子：
3.5
作者：
Lopez, Javier;Fernandez-Pisonero, Isabel;Garcia-Rodriguez, Carmen
通讯作者：
Garcia-Rodriguez, Carmen
影响因子：
37.8
作者：
Miller JD;Weiss RM;Serrano KM;Brooks RM 2nd;Berry CJ;Zimmerman K;Young SG;Heistad DD
通讯作者：
Heistad DD
影响因子：
4.8
作者：
Babelova, Andrea;Moreth, Kristin;Schaefer, Liliana
通讯作者：
Schaefer, Liliana
影响因子：
4.1
作者：
HILDEBRAND, A;ROMARIS, M;RUOSLAHTI, E
通讯作者：
RUOSLAHTI, E