Fibroblast growth factor-2 induces osteogenic differentiation through a Runx2 activation in vascular smooth muscle cells
Fibroblast growth factor-2 induces osteogenic differentiation through a Runx2 activation in vascular smooth muscle cells
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DOI：
10.1016/j.bbrc.2009.11.038
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发表时间：
2010-04-02
影响因子：
3.1
通讯作者：
Kurabayashi, Masahiko
中科院分区：
文献类型：
--
作者：
Nakahara, Takehiro;Sato, Hiroko;Kurabayashi, Masahiko
骨相关蛋白和成骨细胞转录因子Runx 2在动脉细胞中的表达与血管钙化的发生有关。然而，在血管平滑肌细胞（VSMC）中Runx 2介导的成骨细胞程序激活的上游信号传导知之甚少。我们研究了成纤维细胞生长因子-2（FGF-2），一种重要的骨形成调节因子，对VSMC成骨分化的影响。用FGF-2刺激培养的大鼠主动脉SMC（RASMC）诱导成骨细胞标志物骨桥蛋白（OPN）和骨钙素的表达。荧光素酶分析表明FGF-2诱导骨细胞特异性元件（OSE）依赖性转录。通过siRNA下调Runx 2抑制RASMC中OPN基因的基础和FGF-2刺激的表达。FGF-2在RASMC中产生过氧化氢，如通过荧光探针所评估的。FGF-2对OPN表达的诱导作用不仅被PD 98059（MEK 1抑制剂）和PP 1（c-Src抑制剂）抑制，而且被抗氧化剂抑制。N-乙酰半胱氨酸。FGF-2处理的RASMC的核提取物显示Runx 2与其靶序列的DNA结合增加。免疫组化显示FGF受体1和Runx 2在人冠状动脉粥样硬化切除标本和钙化主动脉组织中共定位表达。总之，这些结果表明，FGF-2通过丝裂原活化蛋白激酶（MAPK）依赖性和氧化应激敏感性信号通路激活Runx 2，在诱导VSMC成骨细胞分化中发挥作用。(C)2009 Elsevier Inc. All rights reserved.
Expression of bone-associated proteins and osteoblastic transcription factor Runx2 in arterial cells has been implicated in the development of vascular calcification. However, the signaling upstream of the Runx2-mediated activation of osteoblastic program in vascular smooth muscle cells (VSMC) is poorly understood. We examined the effects of fibroblast growth factor-2 (FGF-2), an important regulator of bone formation, on osteoblastic differentiation of VSMC. Stimulation of cultured rat aortic SMC (RASMC) with FGF-2 induced the expression of the osteoblastic markers osteopontin (OPN) and osteocalcin. Luciferase assays showed that FGF-2 induced osteocyte-specific element (OSE)-dependent transcription. Downregulation of Runx2 by siRNA repressed the basal and FGF-2-stimulated expression of the OPN gene in RASMC. FGF-2 produced hydrogen peroxide in RASMC, as evaluated by fluorescent probe. Induction of OPN expression by FGF-2 was inhibited not only by PD98059 (MEK1 inhibitor) and PP1 (c-Src inhibitor), but also by an antioxidant. N-acetyl cysteine. Nuclear extracts from FGF-2-treated RASMC exhibited increased DNA-binding of Runx2 to its target sequence. lmmunohistochemistry of human coronary atherectomy specimens and calcified aortic tissues showed that expression of FGF receptor-1 and Runx2 was colocalized. In conclusion, these results suggest that FGF-2 plays a role in inducing osteoblastic differentiation of VSMC by activating Runx2 through mitogen-activated protein kinase (MAPK)-dependent- and oxidative stress-sensitive-signaling pathways. (C) 2009 Elsevier Inc. All rights reserved.