title: Responsiveness to androgens and effectiveness of antisense oligonucleotides against the androgen receptor on human epidermal keratinocytes is dependent on the age of the donor and the location of cell origin.
abstract: Local androgen excess has been associated with attenuation of wound healing in elderly individuals and with a decline in permeability barrier homeostasis in adult human skin. In this study we have applied specific antisense oligonucleotides, whose activity has already been investigated in SZ95 sebocytes, to inactivate transiently the androgen receptor in a reconstituted epidermis model and in primary human epidermal keratinocytes of different origin (breast, abdomen, foreskin) and donor age (females, 30- and 60-year-old). Further a possible interaction between blockage of androgen receptor and the expression of tissue inhibitors of matrix metalloproteinases was investigated. Androgen receptor levels were similar in pooled keratinocytes of the two age groups. Cell transfection with antisense oligonucleotides against the androgen receptor resulted in decreasing protein levels detected in all epidermal keratinocytes tested, whereas cells of aged donors (60-year-old) exhibited a stronger response than cells of young individuals (30-year-old). Keratinocytes from aged donors also responded to androgens with a stronger regulation of proliferation than keratinocytes of young individuals. The pattern of the androgen-induced response was dependent on the skin region of keratinocyte origin. The expression levels of tissue inhibitor of matrix metalloproteinase-1 were not age-related. Our results demonstrate an enhanced androgen sensitivity of keratinocytes from aged individuals associated with an origin-specific type of response.
authors.affiliation: Laboratory of Biogerontology, Dermato-Pharmacology and Dermato-Endocrinology, Institute of Clinical Pharmacology and Toxicology, Campus Benjamin Franklin, Charité Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fimmel
authors.forename: R
authors.initials: R
authors.lastname: Kurfurst
authors.forename: F
authors.initials: F
authors.lastname: Bonté
authors.forename: C C
authors.initials: CC
authors.lastname: Zouboulis
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology*; D002675:Child, Preschool; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D015595:Skin Aging / Q000502:physiology; D014019:Tissue Donors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D020858:Tissue and Organ Harvesting
chemical_list: D059002:Androgen Receptor Antagonists; D000728:Androgens; D016376:Oligonucleotides, Antisense; D011944:Receptors, Androgen; D019715:Tissue Inhibitor of Metalloproteinase-1