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Engineering insulin‐like growth factor‐1 for local delivery
Author(s) -
Tokunou Tomotake,
Miller Rachel,
Patwari Parth,
Davis Michael E.,
Segers Vincent F. M.,
Grodzinsky Alan J.,
Lee Richard T.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.07-100925
Subject(s) - growth factor , chondrocyte , microbiology and biotechnology , cartilage , proteoglycan , chemistry , insulin like growth factor , biology , receptor , biochemistry , extracellular matrix , anatomy
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 poten tial, 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 activ ity due to the heparin‐binding domain. Because carti lage 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 ex plants 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.— Tokunou, T., Miller, R., Patwari, P., Davis, M. E., Segers, V. F. M., Grodzinsky, A. J., Lee, R. T. Engineering insulin‐like growth factor‐1 for local delivery. FASEB J. 22, 1886–1893 (2008)