Mar. 31, 1999 ANN ARBOR---That golden tan may look terrific, but its cost to your skin---premature aging, wrinkles, sags, blotches, and an increased risk of skin cancer---may be more than you want to pay. While it is well known that ultraviolet radiation from the sun has many effects on skin, scientists still don't fully understand how UV causes so much damage.
University of Michigan scientists have discovered an important new piece of the puzzle, however, which they describe in an article to be published in this week's Nature Medicine.
"We found that ultraviolet irradiation blocks the ability of skin cells to recognize and respond to an essential nutrient called retinoic acid, which skin cells make from vitamin A or retinol," said John J. Voorhees, M.D., the Duncan and Ella Poth Distinguished Professor of Dermatology in the U-M Medical School. "The inability to respond to retinoic acid triggers a cascade of biochemical changes that upsets the normal balance between healthy and dying skin cells. In essence, UV causes a functional vitamin A deficiency in human skin.
"We also found that pretreating skin with retinoic acid---the active form of vitamin A---before UV exposure limits the extent of the harmful biochemical changes."
According to Gary J. Fisher, Ph.D., U-M senior associate research scientist in dermatology and the study's co-author, UV causes a major loss of retinoic acid receptors found in human skin cells. "Retinoic acid receptors are the molecular mediators of the biological actions of vitamin A. When retinoic acid receptors are lost, it is as if the skin has no vitamin A," Fisher explained. "This is a bad situation because vitamin A is required for normal skin development and function. Retinoic acid receptors, when activated by retinoic acid, transfer genetic instructions from DNA to the cell's protein-producing factory telling it to assemble proteins needed for skin cell function.
"Eight hours after skin was exposed to UV radiation in our study, amounts of retinoic acid receptor messenger RNA and protein were as much as 70 percent lower than control levels. They remained below normal levels for more than 24 hours after exposure," Fisher said. "When skin was pre-treated with retinoic acid and then exposed to UV radiation, the amount of messenger RNA and protein still dropped, but it rebounded to normal levels within 16 hours. Applying retinoic acid after UV exposure had no effect."
Voorhees added that when the biochemical retinoic acid receptor pathway is shut down, other dangerous skin changes---which also occur in response to UV exposure---can proceed unchecked. This process was first described by Voorhees, Fisher and their colleagues, in a series of articles published in Nature, New England Journal of Medicine, and Journal of Clinical Investigation.
"In this process, UV activates a protein complex called AP-1, which causes production of large amounts of enzymes called matrix metalloproteinases or MMPs," Voorhees explained. "These MMPs break apart and degrade collagen and elastin, the major structural materials in skin. Although the broken-down collagen and elastin are replaced, the repair process is imperfect. This imperfect repair results in a tiny defect in the skin. With repeated UV exposures, the defect grows and eventually results in the wrinkled appearance of sun-damaged skin. In addition, the biochemical changes associated with activation of AP-1 and production of MMPs promote skin cancer."
Although additional research will be needed to completely understand the complex relationship between the retinoic acid receptor pathway and the pathway responsible for producing enzymes that destroy skin collagen, Voorhees and his colleagues believe the two may exist in a state of dynamic balance. This dynamic balance may be necessary to maintain healthy skin. "However, if the retinoic acid receptor pathway is disabled by UV radiation, the destructive pathway has free rein to inflict a great deal of damage," Voorhees said.
Understanding how these two biochemical pathways work in human skin may lead to new medications or treatments that could block the harmful effects of UV radiation. "Our findings suggest that applying retinoic acid or retinol to skin before going out in the sun might be beneficial. However, before vitamin A or retinoic acid can be recommended as a preventive against sun damage, formal clinical trials must be performed to know whether this notion is correct," Voorhees added.
Until then, Voorhees emphasized that the U-M study reinforces the importance of protecting skin from UV exposure. "Daily exposure to UV radiation---even amounts too small to produce skin redness---is particularly dangerous, because the skin never has time to restore normal levels of retinoic acid receptors."
In addition to Voorhees and Fisher, co-investigators on the U-M study were ZengQuan Wang, Mohamed Boudjelal and Sewon Kang all from the Department of Dermatology in the U-M Health System. The U-M holds a patent on the use of retinoic acid or retinol to prevent wrinkles and skin damage caused by UV exposure from the sun. The research was funded by the Babcock Endowment for Dermatological Research, the Dermatology Foundation (SK) and the Johnson & Johnson Corporation.
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