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-α) 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-α 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-α 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-α in
keloid fibroblasts compared to control skin fibroblasts (p < 0.001). Inhibition of FAP-α/DPPIV activity using the irreversible inhibitor H(2)N-Gly-Pro diphenylphosphonate reduced the increased invasiveness of
keloid fibroblasts (p < 0.001) indicating that
keloid invasion may be partly FAP-α/DPPIV mediated. FAP-α/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-α and DPPIV in the invasive behavior of
keloids. FAP-α and DPPIV may increase the invasive capacity of
keloid fibroblasts rather than by modulating
inflammation or ECM production. Since FAP-α expression is restricted to reactive fibroblasts in wound healing and normal adult tissues are generally FAP-α negative, inhibiting FAP-α/DPPIV activity may be a novel treatment option to prevent
keloid progression.