Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation
Language: 
English
Abstract: 

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.

Author(s): 
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
Item Type: 
Journal Article
Publication Title: 
Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research
Journal Abbreviation: 
J. Bone Miner. Res.
Publication Date: 
Nov 2010
Publication Year: 
2010
Pages: 
2447-2459
Volume: 
25
Issue: 
11
ISSN: 
1523-4681
DOI: 
10.1002/jbmr.133
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 20499340 PMCID: PMC3179288

Turabian/Chicago Citation

Liang Chen, Wei Jiang, Jiayi Huang, Bai-Cheng He, Guo-Wei Zuo, Wenli Zhang, Qing Luo, Qiong Shi, Bing-Qiang Zhang, Eric R. Wagner, Jinyong Luo, Min Tang, Christian Wietholt, Xiaoji Luo, Yang Bi, Yuxi Su, Bo Liu, Stephanie H. Kim, Connie J. He, Yawen Hu, Jikun Shen, Farbod Rastegar, Enyi Huang, Yanhong Gao, Jian-Li Gao, Jian-Zhong Zhou, Russell R. Reid, Hue H. Luu, Rex C. Haydon, Tong-Chuan He and Zhong-Liang Deng. Nov 2010. "Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation." Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 25: 11: 2447-2459. 10.1002/jbmr.133.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1002/jbmr.133 | issn = 1523-4681 | volume = 25 | pages = 2447-2459 | last = Chen | first = Liang | coauthors = 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 | title = Insulin-like growth factor 2 (IGF-2) potentiates BMP-9-induced osteogenic differentiation and bone formation | journal = Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research | date = Nov 2010 | pmid = | pmc = }} </ref>