Oxidized low-density lipoprotein acts synergistically with β-glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells
Oxidized low-density lipoprotein acts synergistically with β-glycerophosphate to induce osteoblast differentiation in primary cultures of vascular smooth muscle cells
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DOI：
10.1002/jcb.21812
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发表时间：
2008-09-01
影响因子：
4
通讯作者：
Shaughnessy, Stephen G.
中科院分区：
文献类型：
--
作者：
Bear, Mackenzie;Butcher, Martin;Shaughnessy, Stephen G.
先前的研究已经将成骨细胞特异性标记定位于钙化动脉粥样硬化病变部位。因此，我们决定使用已建立的血管钙化体外模型，以证实早期报道的氧化低密度脂蛋白（oxLDL）促进血管平滑肌细胞的成骨分化。用β-甘油磷酸盐处理原代牛主动脉平滑肌细胞（BASMCs）发现诱导成骨细胞分化的时间依赖性增加。相反，当BASMCs在单独存在oxLDL的情况下培养时，没有观察到效果。然而，当BASMCs在β-甘油磷酸盐和oxLDL共同存在的情况下培养时，β-甘油磷酸盐诱导成骨细胞分化的能力显着增强。在试图解决这种效应发生的机制中，我们研究了β-甘油磷酸盐和oxLDL对已知对成骨细胞分化至关重要的几种途径的影响。令人惊讶的是，发现单独的β-甘油磷酸盐通过诱导Smad 1/5/8活化和Runx 2表达来增强Osterix（Osx）表达。相反，oxLDL不影响Smad 1/5/8激活或Runx 2激活，而是以细胞外信号调节激酶1和2（Erk 1和2）依赖的方式增强β-甘油磷酸诱导的Osx表达和成骨细胞分化。综合考虑，这些发现表明oxLDL可能促进体内成骨分化和血管钙化的合理机制。
Previous studies have localized osteoblast specific markers to sites of calcified atherosclerotic lesions. We therefore decided to use an established in vitro model of vascular calcification in order to confirm earlier reports of oxidized low-density lipoprotein (oxLDL) promoting the osteogenic differentiation of vascular smooth muscle cells. Treatment of primary bovine aortic smooth muscle cells (BASMCs) with beta-glycerophosphate was found to induce a time-dependent increase in osteoblast differentiation. In contrast, no effect was seen when BASMCs were cultured in the presence of oxLDL alone. However, when the BASMCs were cultured in the presence of both beta-glycerophosphate and oxLDL, beta-glycerophosphate's ability to induce osteoblast differentiation was significantly enhanced. In an attempt to resolve the mechanism by which this effect was occurring, we examined the effect of beta-glycerophosphate and oxLDL on several pathways known to be critical to the differentiation of osteoblasts. Surprisingly, beta-glycerophosphate alone was found to enhance Osterix (Osx) expression by inducing both Smad 1/5/8 activation and Runx2 expression. In contrast, oxLDL did not affect either Smad 1/5/8 activation or Runx2 activation but rather, it enhanced both beta-glycerophosphate-induced Osx expression and osteoblast differentiation in an extracellular signal-regulated kinase 1 and 2 (Erk 1 and 2) -dependent manner. When taken together, these findings suggest a plausible mechanism by which oxLDL may promote osteogenic differentiation and vascular calcification in vivo.