Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2.
Biglycan induces the expression of osteogenic factors in human aortic valve interstitial cells via Toll-like receptor-2.
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DOI：
10.1161/atvbaha.112.300116
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Meng X
中科院分区：
文献类型：
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作者：
Song R;Zeng Q;Ao L;Yu JA;Cleveland JC;Zhao KS;Fullerton DA;Meng X
虽然双糖蛋白聚糖和氧化低密度脂蛋白（oxLDL）的积累已被观察到在钙化，狭窄的主动脉瓣，其在钙化的主动脉瓣疾病的发病机制中的作用知之甚少。我们假设可溶性双糖链通过Toll样受体（TLR）2和TLR 4诱导人主动脉瓣间质细胞（AVIC）的成骨反应，并介导oxLDL的促成骨作用。狭窄瓣膜的AVIC表达较高水平的双糖链蛋白聚糖。用双糖蛋白聚糖刺激正常瓣膜的细胞增加了骨形态发生蛋白-2（BMP-2）和碱性磷酸酶（ALP）在所检查的软骨形成/成骨标志物中的表达，并引起钙沉积物的积累。TLR 2沉默，而不是TLR 4沉默，降低BMP-2和ALP水平后，双糖蛋白聚糖刺激，虽然免疫共沉淀显示，双糖蛋白聚糖intercts与TLR 2和TLR 4。双糖蛋白聚糖可诱导ERK 1/2、p38 MAPK和NF-κB磷酸化。抑制ERK 1/2可显著降低双糖链蛋白聚糖对BMP-2和ALP表达的上调，而抑制p38 MAPK或NF-κB则具有中等程度的作用。用oxLDL刺激AVIC上调双糖蛋白聚糖的表达和释放。双糖链蛋白聚糖的敲低中和降低了oxLDL对BMP-2和ALP表达的影响。细胞外可溶性双糖链主要通过TLR 2诱导人AVIC中BMP-2和ALP的表达，并有助于oxLDL的促成骨作用。这些发现强调了可溶性双糖蛋白聚糖和oxLDL在钙化性主动脉瓣疾病发展中的潜在作用。
While biglycan and oxidized low-density lipoprotein (oxLDL) accumulation has been observed in calcific, stenotic aortic valves, their role in the pathogenesis of calcific aortic valve disease is poorly understood. We hypothesized that soluble biglycan induces the osteogenic response in human aortic valve interstitial cells (AVICs) via Toll-like receptor (TLR) 2 and TLR4, and mediates the pro-osteogenic effect of oxLDL. AVICs of stenotic valves express higher levels of biglycan. Stimulation of cells from normal valves with biglycan increased the expression of bone morphogenetic protein-2 (BMP-2) and alkaline phosphatase (ALP) among the chondrogenic/osterogenic markers examined, and caused accumulation of calcium deposits. TLR2 silencing, but not TLR4 silencing, reduced BMP-2 and ALP levels following biglycan stimulation although co-immunoprecipitation revealed that biglycan intercts with both TLR2 and TLR4. Biglycan induced the phosphorylation of ERK1/2, p38 MAPK and NF-κB. Inhibition of ERK1/2 markedly reduced the up-regulation of BMP-2 and ALP expression by biglycan while inhibition of p38 MAPK or NF-κB had a moderate effect. Stimulation of AVICs with oxLDL up-regulated biglycan expression and release. Knockdown neutralization of biglycan reduced the effect of oxLDL on BMP-2 and ALP expression. Extracellular soluble biglycan induces the expression of BMP-2 and ALP in human AVICs primarily via TLR2 and contributes to the the pro-osteogenic effect of oxLDL. These findings highlight the potential role of soluble biglycan and oxLDL in the development of calcific aortic valve disease.