Hypertrophic Scar Fibroblasts Have Increased Connective Tissue Growth Factor Expression after Transforming Growth Factor-β Stimulation

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Background:Hypertrophic scars and keloids respond to dermal disruption with excessive collagen deposition and increased transforming growth factor (TFG)-β expression. Connective tissue growth factor (CTGF) is a downstream mediator of TGF-β activity that is associated with scar and fibrosis. The authors hypothesize that there is increased expression of CTGF by hypertrophic scar and keloid fibroblasts in response to TGF-β stimulation.Methods:Primary fibroblasts were isolated in culture from human hypertrophic scar (n = 2), keloid (n = 2), and normal skin (n = 2). After 18 hours of serum starvation, the cells were stimulated with 10 ng/ml of TGF-β1, TGF-β2, and TGF-β3 for 24 hours. Quantitative real-time polymerase chain reaction was performed on extracted RNA samples to assay for CTGF mRNA expression.Results:Baseline CTGF expression was increased 20-fold in unstimulated hypertrophic scar fibroblasts and 15-fold in keloid fibroblasts compared with normal fibroblasts. CTGF expression increased greater than 150-fold when stimulated with TGF-β1 (p < 0.002) and greater than 100-fold when stimulated by TGF-β2 or TGF-β3 compared with normal fibroblasts (p < 0.02 and p < 0.002, respectively). CTGF expression was greatest after TGF-β1 stimulation in hypertrophic scar fibroblasts compared with TGF-β2 (p < 0.04) and TGF-β3 (p < 0.02). Keloid fibroblast CTGF expression also increased greater than 100-fold after stimulation with TGF-β1 (p = 0.16) and greater than 75-fold after addition of TGF-β2 and TGF-β3 (p = 0.06 and p = 0.22, respectively).Conclusions:Hypertrophic scar fibroblasts have both intrinsic up-regulation of CTGF transcription and an exaggerated capacity for CTGF transcription in response to TGF-β stimulation. These data suggest that blockage of CTGF activity may reduce pathologic scar formation.

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