HOUSTON - Researchers at The University of Texas M. D.
Anderson Cancer Center simultaneously have resolved a controversy over the cause
of psoriasis and developed the first mouse model that fully mimics the human
disorder. What's more, the scientists have demonstrated they can block the
signals that lead to psoriasis in their mouse model with a
topical skin treatment that
can prevent new outbreaks as well as treat existing psoriatic plaques.
"We have developed a mouse model that exhibits all the major
features of human psoriatic lesions and shown we can reverse those steps," said
John DiGiovanni, Ph.D., the study's principal investigator and director of M. D.
Anderson's Department of Carcinogenesis. "We may have found an entirely new
treatment option for psoriasis."
The study, which appears in the January 2005 issue of the
journal Nature Medicine, available on-line Dec. 12, shows a protein called STAT3
is a crucial initiator of psoriasis and must be present and activated for
psoriasis to develop in their mouse model.
Psoriasis is a chronic condition in which patches of skin
become inflamed and develop itchy red, flaky scales. Areas of the body most
affected include the scalp, elbows, knees, and lower back. Psoriasis affects
about two percent of people worldwide, with men and women equally susceptible.
Current treatment for psoriasis focuses on reducing inflammation and slowing
down the rapid growth and shedding of skin cells called keratinocytes. There is
no effective curative treatment for the underlying condition, according to
DiGiovanni.
"There has been an ongoing controversy about whether the
primary defect in psoriasis is in the immune system or in the keratinocytes,"
says DiGiovanni. "We may have found the link - the change in keratinocytes that
cooperates with the immune system cells necessary for development of human
psoriasis."
The researchers became interested in STAT3 when they learned
it was associated with wound healing, a process that shares many of the same
molecular features with psoriasis and with cancer.
DiGiovanni's research team has recently shown that STAT3 is
involved in the development of skin cancer and began investigating its role in
psoriasis, another disease in which skin cells grow inappropriately.
STAT3 belong to a class of proteins called transcription
factors, potent proteins that can set off a cascade of events by simultaneously
activating many genes. In the case of STAT3, activation leads to the production
of growth-promoting and cell survival proteins. Activated STAT3 is essential in
normal skin to promote wound healing. When the healing process is complete,
normal STAT3 returns to its inactive form. But when it fails to turn off, the
wound healing process continues and skin cells proliferate.
The researchers first looked for activated STAT3 in the skin
of psoriasis patients and found high levels of activated STAT3 in psoriasis
lesions in 19 of 21 patients. Based on this observation, the researchers decided
to develop a mouse model in which the gene that encodes STAT3 is always turned
on in the keratinocyte skin cells. When the genetically altered mice were born
they looked relatively normal, but by the time they were two weeks old, they
began to develop scaly patches on their tails that sometimes spread to their
lower back. When the scientists examined skin samples from the scaly patches
they discovered that the patches mimicked human psoriasis very closely.
"This mouse model recapitulated all of the major epidermal and
immunological features of human psoriasis, something that other animal models
fail to do," said DiGiovanni.
