Keloid scars are common benign fibroproliferative reticular dermal lesions
with unknown etiology and ill-defined management with high rate of recurrence
post surgery. The progression of keloids is characterized by increased
deposition of extracellular matrix proteins, invasion into the surrounding
healthy skin and inflammation. Fibroblasts are considered to be the key cellular
mediators of fibrogenesis in keloid scars. Fibroblast activation protein alpha
(FAP-á) and dipeptidyl peptidase IV (DPPIV) are proteases located at the plasma
membrane promoting cell invasiveness and tumor growth and have been previously
associated with keloid scars.
Therefore, in this study we analyzed in
further detail the expression of FAP-á in keloid fibroblasts compared to control
skin fibroblasts. Dermal fibroblasts were obtained from punch-biopsies from the
active margin of four keloids and four control skin samples. Flow cytometry was
used to analyze FAP-á expression and the CytoSelect® 24-Well Collagen I Cell
Invasion Assay was applied to study fibroblast invasion. Secretion of
extracellular matrix (ECM) proteins was investigated by multiplexed
particle-based flow cytometric assay and enzyme-linked immunosorbent assay. We
found an increased expression of FAP-á in keloid fibroblasts compared to control
skin fibroblasts (p < 0.001). Inhibition of FAP-á/DPPIV activity using the
irreversible inhibitor H2N-Gly-Pro diphenylphosphonate reduced the increased
invasiveness of keloid fibroblasts (p < 0.001) indicating that keloid
invasion may be partly FAP-á/DPPIV mediated. FAP-á/DPPIV inhibition had no
effect, (a) on the synthesis of the ECM proteins procollagen type I C-terminal
peptide and fibronectin, (b) on the production of fibroblast growth factor or
vascular endothelial growth factor, (c) on the expression of the proinflammatory
cytokines interleukin-6 (IL-6), interleukin 8 (IL-8) or monocyte chemotactic
protein-1. These results suggest a potential role for FAP-á and DPPIV in the
invasive behavior of keloids. FAP-á and DPPIV may increase the invasive capacity
of keloid fibroblasts rather than by modulating inflammation or ECM production.
Since FAP-á expression is restricted to reactive fibroblasts in wound healing
and normal adult tissues are generally FAP-á negative, inhibiting FAP-á/DPPIV
activity may be a novel treatment option to prevent keloid progression.
(Fonte: Archives of Dermatological Research)
Dr.ssa Adele Sparavigna
Specialista in Dermatologia e
Venereologia