Insulin-like Growth Factor 2 (IGF-2) Potentiates BMP-9-Induced Osteogenic Differentiation and Bone Formation

• Type of Material: Article
• Authors: Liang Chen, University of Chicago; Wei Jiang, University of Chicago; Jiayi Huang, University of Chicago; Bai-Cheng He, University of Chicago; Guo-Wei Zuo, University of Chicago; Wenli Zhang, University of Chicago; Qing Luo, University of Chicago; Qiong Shi, University of Chicago; Bing-Qiang Zhang, University of Chicago; Eric Wagner, Emory University; Jinyong Luo, University of Chicago; Min Tang, Chinese Minist Educ; Christian Wietholt, University of Chicago; Xiaoji Luo, University of Chicago; Yang Bi, University of Chicago; Yuxi Su, University of Chicago; Bo Liu, University of Chicago; Stephanie H. Kim, University of Chicago; Connie J. He, University of Chicago
• Language: English
• Date: 2010-11-01
• Publisher: American Society for Bone and Mineral Research
• Publication Version: Final Published Version
• Copyright Statement: ©2010 American Society for Bone and Mineral Research.
• License: Creative Commons Attribution 2.5 Generic
• Final Published Version (URL): http://dx.doi.org/10.1002/jbmr.133
• Title of Journal or Parent Work: Journal of Bone and Mineral Research
• ISSN: 0884-0431
• Volume: 25
• Issue: 11
• Start Page: 2447
• End Page: 2459
• Grant/Funding Information: This work was supported in part by research grants from the Brinson Foundation (TCH), the National Institutes of Health (CA106569, AT004418, AR50142, and AR054381 to TCH, RCH, and HHL), the 863 Program of the Ministry of Science and Technology of China (2007AA2z400 to CL, TCH, and ZLD), the Natural Science Foundation of China (30901530 to XL, 30800658 to JL, and 30772211 to ZLD), and the Natural Science Foundation Project of Chongqing Science and Technology Commission (2008BB5396 to LC and MT and 2009BB5060 to JL).
• Keywords: Science & Technology; BMP 9; HEPATIC PROGENITOR CELLS; OSTEOBLAST DIFFERENTIATION; OSTEOBLASTIC DIFFERENTIATION; TRANSGENIC MICE; BONE FORMATION; MOUSE; FRACTURE HEALING; MORPHOGENETIC PROTEINS; MARROW STROMAL CELLS; RECOMBINANT ADENOVIRUSES; Endocrinology & Metabolism; GENE; IGF 2; MESENCHYMAL STEM-CELLS; Life Sciences & Biomedicine; PHOSPHATIDYLINOSITOL 3-KINASE
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

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.