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Am J Physiol Cell Physiol 284: C860-C869, 2003. First published December 21, 2002; doi:10.1152/ajpcell.00350.2002
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Vol. 284, Issue 4, C860-C869, April 2003

Role of IGF system of mitogens in the induction of fibroblast proliferation by keloid-derived keratinocytes in vitro

Toan-Thang Phan1, Ivor Jiun Lim2, Boon Huat Bay3, Robert Qi4, Michael Thornton Longaker5, Seng-Teik Lee6, and Hung Huynh7

1 National Burns Centre, 6 Department of Plastic Surgery, Singapore General Hospital, Singapore 169608; 2 Division of Plastic Surgery, Departments of Surgery and 3 Anatomy, National University of Singapore, Singapore 119260; 4 Institute of Molecular and Cell Biology, Singapore 117609; 7 Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre of Singapore, Singapore 169610; and 5 Department of Surgery, Stanford University, Stanford, California 94305-5148

Keloids are proliferative dermal growths representing a pathological wound-healing response. We report high proliferation rates in normal (NF) and keloid-derived fibroblasts (KF) cocultured with keloid-derived keratinocytes (KK). IGF binding protein (IGFBP)-3 mRNA and secreted IGFBP-3 in conditioned media were increased in NF cocultured with KK compared with NF but markedly reduced in KF cocultured with KK or normal keratinocytes (NK). IGFBP-2 and IGFBP-4 mRNA levels were elevated, whereas IGFBP-5 mRNA was decreased in KF cocultured with KK or NK. Significant increases in IGFBP-2 and -4 mRNA in KF cocultured with KK did not correlate with protein secretion. Downstream IGF signaling cascade components, phospho-Raf, phospho-MEK1/2, phospho-MAPK, PI-3 kinase, phospho-Akt, and phospho-Elk-1, were elevated in KF cocultured with KK. Addition of recombinant human IGFBP-3 or antibodies against IGF-I or IGF-IR significantly inhibited proliferation of KF. The bioavailability of IGF-I may be related to the levels of IGFBP-3 produced, which in turn influences KF proliferation, suggesting that modulation of IGF-I, IGF-IR, and IGFBP-3, individually or in combination, may represent novel approaches to the treatment of keloids.

insulin-like growth factor; coculture




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