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Title
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Engineering insulin-like growth factor-1 for local delivery
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Author
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Abstract
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| Insulin-like growth factor-1 (IGF-1) is a small protein that promotes cell survival and growth, often acting over long distances. Although for decades IGF-1 has been considered to have therapeutic potential, systemic side effects of IGF-1 are significant, and local delivery of IGF-1 for tissue repair has been a long-standing challenge. In this study, we designed and purified a novel protein, heparin-binding IGF-1 (Xp-HB-IGF-1), which is a fusion protein of native IGF-1 with the heparin-binding domain of heparin-binding epidermal growth factor-like growth factor. Xp-HB-IGF-1 bound selectively to heparin as well as the cell surfaces of 3T3 fibroblasts, neonatal cardiac myocytes and differentiating ES cells. Xp-HB-IGF-1 activated the IGF-1 receptor and Akt with identical kinetics and dose response, indicating no compromise of biological activity due to the heparin-binding domain. Because cartilage is a proteoglycan-rich environment and IGF-1 is a known stimulus for chondrocyte biosynthesis, we then studied the effectiveness of Xp-HB-IGF-1 in cartilage. Xp-HB-IGF-1 was selectively retained by cartilage explants and led to sustained chondrocyte proteoglycan biosynthesis compared to IGF-1. These data show that the strategy of engineering a long-distance growth factor like IGF-1 for local delivery may be useful for tissue repair and minimizing systemic effects. |
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Language
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English
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Source (journal)
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The FASEB journal / Federation of American Societies for Experimental Biology. - Bethesda, Md
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Publication
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Bethesda, Md
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2008
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ISSN
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0892-6638
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DOI
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10.1096/FJ.07-100925
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Volume/pages
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22
:6
(2008)
, p. 1886-1893
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ISI
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000256352700028
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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