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

Abstract

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.

Clinical and epidemiological analysis of keloids in Chinese patients

“…It is characterized by an excessive accumulation of extracellular matrix and especially by overabundant collagen formation, which has escaped the boundaries of the original wound to invade the surrounding normal skin. [24] Keloids cause esthetically unappealing and functional disturbances, leading patients' psychological and physical distress. The prevalence of keloids varies among different populations, and it involves a higher proportion of African-Americans and Asians, especially in dark-skinned individuals.…”

Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor

“…Indeed, insulin-like growth factor 1, which has been reported to be present in keloids, also causes signaling in keratinocytes in vitro and hyperplasia of the epidermis in vivo. [34][35][36] Our findings of the epidermis as the major source of VEGF suggests novel therapies for keloids by inhibiting the production and effect of keratinocyte-derived VEGF. In addition, many of our current modalities for keloids may cause inhibition of angiogenesis, which may account for their effect for patients.…”

WITHDRAWN: Targeting mTORC1/2 with OSI-027 inhibits proliferation and migration of keloid keratinocytes

“…The acquired epidermal tissues were minced, washed, and digested by collagenase I (Sigma-Aldrich, catalog no. C0130) [34]. Digestions (2-5) were neutralized, pooled, and filtered.…”