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

Hypertrophic scars and keloids remain a mystery, at least in terms of finding genetic and biochemical abnormalities that could be treated. While decades of research have been done on many aspects of keloids and hypertrophic scars,1 a specific unifying abnormality has yet to be found. Research into other fibrotic pathologies often suggests paths for investigations of keloids and hypertrophic scars.1 Connective tissue growth factor (CTGF) is an intriguing subject, as it has been implicated in scleroderma, and in diabetic neuropathy, cardiomyopathy, and renal disease.2 CTGF is a member of the CCN (cyr61, ctgf, nov) group of proteins, rich in cysteine.2,3 The marked synergism of transforming growth factor (TGF)and CTGF in increasing experimental fibrosis is especially interesting.3 In clinical plastic surgery, most plastic surgeons assume that there is a spectrum of postwounding collagen synthesis and turnover. Thus normal healing has an initial vigorous growth of connective tissue (the wound is red and nodular), which then diminishes over the next 6 to 12 months.4 Hypertrophic scarring overgrowth which does not resolve, but which stays within the wound boundaries is “worse” proliferation. And keloids, which grow beyond the wound boundary, are “worst” proliferation. So we assume that biochemical abnormalities would follow the same linear spectrum, of normal to worse to worst, with increasing degrees of abnormality. But this is not what the authors have observed. Baseline CTGF was higher in unstimulated hypertrophic scars than in keloids. Response to TGFwas also higher in hypertrophic scars, suggesting that the concept of a linear spectrum of abnormality may not be valid. In contrast, the role of CTGF may be only marginal in scar overgrowth problems, and this is yet to be determined. The experimental tissue culture model poses some concerns. First, cells from different body areas can grow at different rates,5 and ideally comparisons should be made from cells grown from similar anatomical sites. Second, the study was conducted on third passage cells. Primary cell cultures would be more desirable to use in this study, or to study cultures that have undergone the same number of population doublings. Passage as a chronological reference is misleading, as some passages may contain cell populations that have undergone numerous population doublings in a passage, reaching a critical limit of replication sooner than slower dividing populations. Thirdly, because confluent cultures are capable of only limited cell division, a cellular response to TGBmay be compromised and misleading. Fourth, it may be helpful to use a longer than 18-hour starvation time. Especially with confluent cells, an interval of up to 72 hours may be needed to ensure complete removal of serum-derived growth factors. Clearly, the authors have chosen an interesting pathology to examine the role of CTGF, but they and/or others must apply a more critical experimental design to discover the important role of this protein in these fibroproliferative disorders. Critical to the authors’ observations which appear to show that hypertrophic scar fibroblasts have an intrinsic ability to up-regulate CTGF in response to TGFstimulation is that these conclusions were based on a very limited sample size.