Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo.
Ultraviolet radiation from the sun damages human skin, resulting in an old and wrinkled appearance. A substantial amount of circumstantial evidence indicates that photoaging results in part from alterations in the composition, organization, and structure of the collagenous extracellular matrix in the dermis. This paper reviews the authors' investigations into the molecular mechanisms by which ultraviolet irradiation damages the dermal extracellular matrix and provides evidence for prevention of this damage by all-trans retinoic acid in human skin in vivo. Based on experimental evidence a working model is proposed whereby ultraviolet irradiation activates growth factor and cytokine receptors on keratinocytes and dermal cells, resulting in downstream signal transduction through activation of MAP kinase pathways. These signaling pathways converge in the nucleus of cells to induce c-Jun, which heterodimerizes with constitutively expressed c-Fos to form activated complexes of the transcription factor AP-1. In the dermis and epidermis, AP-1 induces expression of matrix metalloproteinases collagenase, 92 kDa gelatinase, and stromelysin, which degrade collagen and other proteins that comprise the dermal extracellular matrix. It is hypothesized that dermal breakdown is followed by repair that, like all wound repair, is imperfect. Imperfect repair yields a deficit in the structural integrity of the dermis, a solar scar. Dermal degradation followed by imperfect repair is repeated with each intermittent exposure to ultraviolet irradiation, leading to accumulation of solar scarring, and ultimately visible photoaging. All-trans retinoic acid acts to inhibit induction of c-Jun protein by ultraviolet irradiation, thereby preventing increased matrix metalloproteinases and ensuing dermal damage.
Fisher
G J
GJ
Department of Dermatology, University of Michigan, Ann Arbor 48109-0609, USA.
Voorhees
J J
JJ
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology*; D008666:Metalloendopeptidases / Q000502:physiology; D011859:Radiography; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*; D012867:Skin / Q000000981:diagnostic imaging; D015595:Skin Aging / Q000187:drug effects* / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D014466:Ultraviolet Rays
D007641:Keratolytic Agents; D018808:Transcription Factor AP-1; D014212:Tretinoin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008666:Metalloendopeptidases