Submitted on July 30, 2002
Accepted on December 31, 1969
The role of the insulin-like growth factor (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 Huynh6*
1 National Burns Centre, Singapore General Hospital, Singapore, Singapore
2 Department of Surgery, National University of Singapore, Singapore, Singapore
3 Department of Anatomy, National University of Singapore, Singapore, Singapore
4 Institute of Molecular and Cell Biology, Singapore, Singapore
5 Department of Surgery, Stanford University, USA, USA
6 Department of Plastic Surgery, Singapore General Hospital, Singapore, Singapore
* To whom correspondence should be addressed. E-mail: cmrhth{at}nccs.com.sg.
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). IGFBP-3 mRNA and secreted IGFBP-3 in conditioned media (CM) were increased in NF cocultured with KK compared with NF, but markedly reduced in KF cocultured with KK or NK. IGFBP-2 and IGFBP-4 mRNA levels were elevated while 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 signalling 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.
