title: Mechanistic effects of long-term ultraviolet B irradiation induce epidermal and dermal changes in human skin xenografts.
abstract: UVB irradiation has been reported to induce photoaging and suppress systemic immune function that could lead to photocarcinogenesis. However, because of the paucity of an UVB-induced photodamaged skin model, precise and temporal mechanism(s) underlying the deleterious effects of long-term UVB exposure on human skin have yet to be delineated. In this study, we established a model using human skin xenografted onto severe combined immunodeficient mice, which were subsequently challenged by repeated UVB irradiation for 6 weeks. Three-dimensional optical image analysis of skin replicas and noninvasive biophysical measurements illustrated a significant increase in skin surface roughness, similar to premature photoaging, and a significant loss of skin elasticity after long-term UVB exposure. Resembling authentically aged skin, UVB-exposed samples exhibited significant increases in epithelial keratins (K6, K16, K17), elastins, and matrix metalloproteinases (MMP-1, MMP-9, MMP-12) as well as degradation of collagens (I, IV, VII). The UVB-induced deterioration of fibrous keratin intermediate filaments was also observed in the stratum corneum. Additionally, similarities in gene expression patterns between our model and chronologically aged skin substantiated the plausible relationship between photodamage and chronological age. Furthermore, severe skin photodamage was observed when neutralizing antibodies against TIMP-1, an endogenous inhibitor of MMPs, were administered during the UVB exposure regimen. Taken together, these findings suggest that our skin xenograft model recapitulates premature photoaged skin and provides a comprehensive tool with which to assess the deleterious effects of UVB irradiation.
authors.affiliation: Kao Biological Science Laboratories, Tochigi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hachiya
authors.forename: Penkanok
authors.initials: P
authors.lastname: Sriwiriyanont
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujimura
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohuchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitahara
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takema
authors.forename: William J
authors.initials: WJ
authors.lastname: Kitzmiller
authors.forename: Marty O
authors.initials: MO
authors.lastname: Visscher
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
authors.forename: Raymond E
authors.initials: RE
authors.lastname: Boissy
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism / Q000528:radiation effects; D020405:Dermis / Q000473:pathology / Q000528:radiation effects*; D004195:Disease Models, Animal; D004548:Elasticity / Q000528:radiation effects; D004549:Elastin / Q000378:metabolism / Q000528:radiation effects; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D007633:Keratins / Q000378:metabolism / Q000528:radiation effects; D020782:Matrix Metalloproteinases / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D016513:Mice, SCID; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015595:Skin Aging / Q000528:radiation effects*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors; D014183:Transplantation, Heterologous; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D007633:Keratins; D003094:Collagen; D004549:Elastin; D020782:Matrix Metalloproteinases