Leptin Promotes the Osteoblastic Differentiation of Vascular Smooth Muscle Cells From Female Mice by Increasing RANKL Expression
Leptin Promotes the Osteoblastic Differentiation of Vascular Smooth Muscle Cells From Female Mice by Increasing RANKL Expression
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瘦素通过增加 RANKL 表达来促进雌性小鼠血管平滑肌细胞的成骨细胞分化。
DOI：
10.1210/en.2013-1298
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发表时间：
2014-02-01
期刊：
影响因子：
4.8
通讯作者：
Liao, Er-Yuan
中科院分区：
文献类型：
--
作者：
Liu, Guan-Ying;Liang, Qiu-Hua;Liao, Er-Yuan
动脉钙化是一个复杂的、主动调控的过程，是血管平滑肌细胞（VSMCs）向成骨细胞分化的结果。瘦素是ob基因的产物，主要调节食物摄入和能量消耗，最近被认为与动脉钙化有关。然而，瘦素对VSMCs成骨分化的影响机制尚不清楚。本研究以钙化血管平滑肌细胞为模型，探讨瘦素与钙化血管平滑肌细胞成骨分化的关系及其信号通路。我们的实验表明，瘦素可增加CVSMC中核因子-κB配体受体激活因子（RANKL）和骨形态发生蛋白4（BMP 4）的表达，以及碱性磷酸酶（ALP）活性、Runt相关转录因子2的表达、钙沉积和矿化结节的形成。用小干扰RNA抑制RANKL可阻断瘦素诱导的CVSMC ALP活性和BMP 4表达。瘦素可激活ERK 1/2和磷脂酰肌醇3激酶（PI 3 K）/Akt信号通路。ERK抑制剂PD 98059和PI 3 K抑制剂LY 294002预处理可阻断瘦素诱导的RANKL表达和ALP活性升高。用小干扰RNA沉默瘦素受体OB-Rb可阻断瘦素诱导的ERK和Akt的激活及RANKL的表达，逆转瘦素对ALP活性的影响。同时，加入Noggin（BMP 4抑制剂）减弱了leptin对ALP活性的影响。这些结果表明瘦素可通过OB-Rb/ERK 1/2/RANKL-BMP 4和OB-Rb/PI 3 K/Akt/RANKL-BMP 4途径促进CVSMCs向成骨细胞分化。
Arterial calcification is a complex and active regulated process, which results from a process of osteoblastic differentiation of vascular smooth muscle cells (VSMCs). Leptin, the product of the ob gene, mainly regulates food intake and energy expenditure and recently has been considered to be correlated with the arterial calcification. However, the mechanisms of the effects of leptin on osteoblastic differentiation of VSMCs are unknown. We used calcifying vascular smooth muscle cells (CVSMCs) as a model to investigate the relationship between leptin and the osteoblastic differentiation of CVSMCs and the signaling pathways involved. Our experiments demonstrated that leptin could increase expression of receptor activator of nuclear factor-κB ligand (RANKL) and bone morphogenetic protein 4 (BMP4), as well as alkaline phosphatase (ALP) activity, runt-related transcription factor 2 expression, calcium deposition, and the formation of mineralized nodules in CVSMCs. Suppression of RANKL with small interfering RNA abolished the leptin-induced ALP activity and BMP4 expression in CVSMCs. Leptin could activate the ERK1/2 and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Furthermore, pretreatment with the ERK inhibitor PD98059 and the PI3K inhibitor LY294002 abolished leptin-induced RANKL expression and blocked the promotion of ALP activity of CVSMCs. Silencing of the leptin receptor OB-Rb with small interfering RNA abolished leptin-induced activation of ERK and Akt and the expression of RANKL and reversed the effects of leptin on ALP activity. Meanwhile, addition of Noggin (the BMP4 inhibitor) blunted the effect of leptin on ALP activity. These results show that leptin can promote osteoblastic differentiation of CVSMCs by the OB-Rb/ERK1/2/RANKL-BMP4 and OB-Rb/PI3K/Akt/RANKL-BMP4 pathways.