Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation.
Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation.
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胰岛素样生长因子 2 (IGF-2) 增强 BMP-9 诱导的成骨分化和骨形成
DOI：
10.1002/jbmr.133
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发表时间：
2010-11
影响因子：
6.2
通讯作者：
Deng, Zhong-Liang
中科院分区：
文献类型：
--
作者：
Chen, Liang;Jiang, Wei;Huang, Jiayi;He, Bai-Cheng;Zuo, Guo-Wei;Zhang, Wenli;Luo, Qing;Shi, Qiong;Zhang, Bing-Qiang;Wagner, Eric R.;Luo, Jinyong;Tang, Min;Wietholt, Christian;Luo, Xiaoji;Bi, Yang;Su, Yuxi;Liu, Bo;Kim, Stephanie H.;He, Connie J.;Hu, Yawen;Shen, Jikun;Rastegar, Farbod;Huang, Enyi;Gao, Yanhong;Gao, Jian-Li;Zhou, Jian-Zhong;Reid, Russell R.;Luu, Hue H.;Haydon, Rex C.;He, Tong-Chuan;Deng, Zhong-Liang
间充质干细胞（MSCs）高效的成骨分化和成骨作用在治疗骨折不愈合方面具有临床应用价值。间充质干细胞是贴壁的骨髓基质细胞，可以自我更新并分化成成骨、软骨、脂肪和肌细胞谱系。骨形态发生蛋白9（BMP-9）是目前发现的最具成骨活性的骨形态发生蛋白之一。在这里，我们研究胰岛素样生长因子2（IGF-2）对BMP-9诱导的骨形成的影响。我们已经发现，内源性IGF-2表达在MSC中是低的。IGF-2的表达可以增强BMP-9诱导的早期成骨标志物碱性磷酸酶（ALP）活性和后期标志物的表达。在干细胞植入试验中，IGF-2已显示出增加BMP-9诱导的异位骨形成。在围产期肢体外植体培养试验中，IGF-2增强BMP-9诱导的软骨内骨化，而IGF-2本身可以促进培养的肢体外植体的肥大软骨细胞区的扩张。IGF拮抗剂IGFBP3和IGFBP4的表达导致IGF-2对BMP-9诱导的ALP活性和基质矿化的作用的抑制。在机制上，IGF-2进一步显示出增强BMP-9诱导的BMPR-Smad报告基因活性和Smad1/5/8核转位。PI3-激酶（PI3K）抑制剂LY294002消除IGF-2对BMP-9介导的成骨信号传导的增强作用，并且可以直接抑制BMP-9活性。这些结果表明，BMP-9交联IGF-2通过PI3K/AKT信号通路在成骨分化的MSC。总之，我们的研究结果表明，BMP-9和IGF-2的组合可以探索作为一种有效的骨再生剂，以治疗大段骨缺损，骨折不愈合，和/或骨质疏松性骨折。© 2010美国骨与矿物质研究学会。
Efficient osteogenic differentiation and bone formation from mesenchymal stem cells (MSCs) should have clinical applications in treating nonunion fracture healing. MSCs are adherent bone marrow stromal cells that can self-renew and differentiate into osteogenic, chondrogenic, adipogenic, and myogenic lineages. We have identified bone morphogenetic protein 9 (BMP-9) as one of the most osteogenic BMPs. Here we investigate the effect of insulin-like growth factor 2 (IGF-2) on BMP-9-induced bone formation. We have found that endogenous IGF-2 expression is low in MSCs. Expression of IGF-2 can potentiate BMP-9-induced early osteogenic marker alkaline phosphatase (ALP) activity and the expression of later markers. IGF-2 has been shown to augment BMP-9-induced ectopic bone formation in the stem cell implantation assay. In perinatal limb explant culture assay, IGF-2 enhances BMP-9-induced endochondral ossification, whereas IGF-2 itself can promote the expansion of the hypertropic chondrocyte zone of the cultured limb explants. Expression of the IGF antagonists IGFBP3 and IGFBP4 leads to inhibition of the IGF-2 effect on BMP-9-induced ALP activity and matrix mineralization. Mechanistically, IGF-2 is further shown to enhance the BMP-9-induced BMPR-Smad reporter activity and Smad1/5/8 nuclear translocation. PI3-kinase (PI3K) inhibitor LY294002 abolishes the IGF-2 potentiation effect on BMP-9-mediated osteogenic signaling and can directly inhibit BMP-9 activity. These results demonstrate that BMP-9 crosstalks with IGF-2 through PI3K/AKT signaling pathway during osteogenic differentiation of MSCs. Taken together, our findings suggest that a combination of BMP-9 and IGF-2 may be explored as an effective bone-regeneration agent to treat large segmental bony defects, nonunion fracture, and/or osteoporotic fracture. © 2010 American Society for Bone and Mineral Research.
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影响因子：
14.8
作者：
Luo, Jinyong;Deng, Zhong-Liang;He, Tong-Chuan
通讯作者：
He, Tong-Chuan
影响因子：
64.5
作者：
BAKER, J;LIU, JP;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A
影响因子：
56.9
作者：
He, TC;Sparks, AB;Kinzler, KW
通讯作者：
Kinzler, KW
影响因子：
30.8
作者：
Fuks, F;Burgers, WA;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
46.9
作者：
Chen, C;Grzegorzewski, KJ;Birse, CE
通讯作者：
Birse, CE