Mechanism of osteogenic induction by FK506 via BMP/Smad pathways
Mechanism of osteogenic induction by FK506 via BMP/Smad pathways
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DOI：
10.1016/j.bbrc.2005.10.024
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发表时间：
2005-12-16
影响因子：
3.1
通讯作者：
Chung, UI
中科院分区：
文献类型：
--
作者：
Kugimiya, F;Yano, F;Chung, UI
FK506是一种免疫抑制剂，通过与FK506结合蛋白12（FKBP 12）结合发挥作用。最近，也有报道称FK506在局部或体外与骨形态发生蛋白（BMP）联合给药时可促进成骨分化，但其潜在机制仍不清楚。本研究最初表明，FK506单独在一个较高的浓度（1 μ M）诱导间充质细胞系，这是抑制腺病毒导入Smad6的成骨分化。FK506在BMP不存在的情况下迅速激活BMP依赖性Smads，并且该激活被Smad6阻断。据报道，FKBP 12的过表达可以阻断BMP I型受体A（BMPRIA）的配体非依赖性激活，抑制FK 506诱导的Smad信号传导，但不能抑制BMP 2诱导的Smad信号传导。BMPRIA和FKBP 12相互结合，并且这种结合被FK506抑制。这些数据表明，FK506通过与FKBP 12相互作用激活BMP受体促进成骨分化。(c)2005年爱思唯尔公司All rights reserved.
FK506 is an immunosuppressant that exerts effects by binding to FK506-binding protein 12 (FKBP12). Recently, FK506 has also been reported to promote osteogenic differentiation when administered locally or in vitro in combination with bone morphogenetic proteins (BMPs), although the underlying mechanism remains unclarified. The present study initially showed that FK506 alone at a higher concentration (1 mu M) induced osteogenic differentiation of mesenchymal cell lines, which was suppressed by adenoviral introduction of Smad6. FK506 rapidly activates the BMP-dependent Smads in the absence of BMPs, and the activation was blocked by Smad6. Overexpression of FKBP 12, which was reported to block the ligand-independent activation of BMP type I receptor A (BMPRIA), suppressed Smad signaling induced by FK506, but not that induced by BMP2. BMPRIA and FKBP12 bound to each other, and this binding was suppressed by FK506. These data suggest that FK506 promotes osteogenic differentiation by activating BMP receptors through interacting with FKBP12. (c) 2005 Elsevier Inc. All rights reserved.