Normalized proliferation of normal and psoriatic keratinocytes by suppression of sAPPalpha-release.
The soluble form of the beta-amyloid precursor protein (sAPPalpha) is known to function in the autocrine regulation of epidermal growth and repair. Here we show that its proteolytic release by alpha-secretase in normal human keratinocytes is susceptible to hydroxamic-acid-based zinc metalloproteinase inhibitors and suppressed by these inhibitors by 80%-90%. As various other growth factors participate in regulating epidermal growth we investigated whether the inhibitor-induced sAPPalpha-deficiency would affect keratinocyte proliferation. At optimal inhibitor concentrations the suppression of sAPPalpha-release was followed by a decline in proliferation by 50%-60%, indicating that sAPPalpha is a major growth factor that cannot be compensated for by other growth factors. This finding was the basis for the treatment of human lesional psoriatic keratinocytes with these inhibitors, which resulted in the normalization of their increased proliferation rates. The reversibility of these effects and the lack of toxicity underline the value of these inhibitors and suggest their therapeutic application in psoriatic skin diseases.
Siemes
Christina
C
Institute of Cell Biology and Bonner Forum Biomedizin, University of Bonn, Ulrich-Haberland-Strasse 61A, 53121 Bonn, Germany.
Quast
Thomas
T
Klein
Elisabeth
E
Bieber
Thomas
T
Hooper
Nigel M
NM
Herzog
Volker
V
D000328:Adult; D000368:Aged; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D001706:Biopsy; D002455:Cell Division; D002478:Cells, Cultured; D010450:Endopeptidases / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology*; D008875:Middle Aged; D011565:Psoriasis / Q000378:metabolism* / Q000473:pathology*; D011994:Recombinant Proteins / Q000378:metabolism; D012995:Solubility
D016564:Amyloid beta-Protein Precursor; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human