Keratinocyte-derived growth factors play a role in the formation of hypertrophic scars

In predisposed individuals, wound healing can lead to hypertrophic scar or keloid formation, characterized by an overabundant extracellular matrix. It has recently been shown that hypertrophic scars are accompanied by abnormal keratinocyte differentiation and proliferation, and significantly increased acanthosis, compared with normal scars. This study addressed the question of whether the development of normal and hypertrophic scars is regulated by differences in the growth factor profiles of both the epidermis and the dermis. The presence of interleukin-1alpha (IL-1alpha), IL-1beta, tumour necrosis factor-alpha (TNF-alpha), platelet-derived growth factor (PDGF), transforming growth factor-beta1 (TGF-beta1), and basic fibroblast growth factor (bFGF) was investigated in biopsies taken from breast reduction scars at 3 and 12 months following surgery. The samples were analysed by immunohistological methods and categorized as scars that remained hypertrophic (HH), became normal (HN) or remained normal after 12 months (NN). The epidermal expression of IL-1alpha was significantly increased in NN scars compared with HN and HH scars 3 and 12 months following operation, whereas the dermal expression showed no difference. PDGF was significantly increased in the dermis of normal scars after 3 months and in both the epidermis and the dermis of hypertrophic scars after 12 months. IL-1beta, TNF-alpha, TGF-beta and bFGF showed no differences. It is hypothesized that impaired production of keratinocyte-derived growth factors, such as IL-1alpha, leads to a decrease in the catabolism of the dermal matrix, whereas augmented epidermal PDGF production leads to increased formation of the dermal matrix in hypertrophic scars. These observations support the possibility that the epidermis is involved in preventing the formation of hypertrophic scars.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.