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. © 2010 American Society for Bone and Mineral Research.
Highlights
Bone is one of a few organs that retain the potential for regeneration into adult life and is the only tissue that can undergo continual remodeling throughout life
As a member of the IGF signaling system, insulin-like growth factor 2 (IGF-2) plays an important role in prenatal growth and development.[27]. IGF-2 transduces its signaling through IGF receptors and activates the phosphatidylinositol-3-kinase (PI3K)/AKT pathway or the mitogen-activated protein kinase (MAPK) pathway.[28]. Igf2 null mice exhibit a 40% decrease in birth weight compared with their wild-type littermates, suggesting an important role of IGF-2 in development.[29,30] We have found that endogenous IGF-2 expression is relatively low in Mesenchymal stem cells (MSCs)
Endogenous IGF-2 expression is low in mesenchymal stem cells, and exogenous IGF-2 expression potentiates bone morphogenetic protein 9 (BMP-9)-induced early osteogenic marker alkaline phosphatase (ALP) activity
Summary
Bone is one of a few organs that retain the potential for regeneration into adult life and is the only tissue that can undergo continual remodeling throughout life. BMP-9 ( known as growth differentiation factor 2, or GDF-2) was first identified in the developing mouse liver,(23) and its possible roles include inducing and maintaining the cholinergic phenotype of embryonic basal forebrain cholinergic neurons,(24) inhibiting hepatic glucose production and inducing the expression of key enzymes of lipid metabolism,(25) and stimulating murine hepcidin 1 expression.[26] the functional role of BMP-9 in the skeletal system remains to be fully understood, the potent osteogenic activity of BMP-9 suggests that it may be used as an efficacious bone-regeneration agent. It is conceivable that other growth factors may act synergistically or enhance BMP-9-induced bone formation
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