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New Clues into Causes of Scleroderma

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Duke Health News 919-660-1306

DURHAM, N.C. -- Using a novel model for scleroderma,
researchers from Duke University Medical Center have discovered
two important insights into this devastating disorder – the
anti-cancer drug paclitaxel (Taxol) may prevent the skin
thickening and small blood vessel destruction that
characterizes the disease. Also, they found that a patient's
own immune system may actually interfere with body's inherent
ability to repair damage, and in particular, damage to small
arteries.

The researchers are so encouraged by the results of their
experiments in mice that they are in the early planning stages
of a clinical trial incorporating their findings in human
patients with the disease.

Scleroderma is a chronic degenerative disease that afflicts
more than 300,000 Americans, primarily women. The
life-threatening disorder is marked by dramatic tissue damage
including hardening of the skin, shrinking of muscles, and
damage to organs and blood vessels. To date, physicians have
been unable to determine what causes the disease, and the
available few therapies, serve primarily to relieve symptoms,
according to the researchers.

"These new insights are critical clues to understanding a
dreadful disease that has so far been impenetrable in terms of
what causes it, by what mechanisms it works and why patients
get so sick," said cardiologist Pascal Goldschmidt, M.D.,
senior member of the research team and chairman of Duke's
Department of Medicine.

The results of the Duke studies were published in the Nov.
1, 2005, edition of Public Library of Science Medicine. The
research was supported by the Scleroderma Research Foundation,
San Francisco.

"While we really don't understand what causes scleroderma,
we suspect that it may be autoimmune in nature, or that the
body's own immune system is involved," said Chunming Dong,
M.D., lead author of the paper "Using a novel mouse model, we
were able to get a much better understanding of possible
mechanisms of the disease that we can use to potentially slow
down or reverse the process of tissue damage."

One of the most characteristic effects of the disease is the
gradual formation of fibrotic tissue, which leaves patients
with disfiguring and painful tightening of the skin.
Additionally, the disease tends to slowly destroy small blood
vessels and capillaries, which are not only present in skin,
but also in internal organs, leaving them vulnerable to
function failure.

It is known that the excessive fibrosis seen in scleroderma
patients is in part the result of an inappropriate activation
of transforming growth factor-beta (TGF-beta), a substance
called a cytokine that regulates the intensity and duration of
the immune response. Too much TGF-beta activity can occur in
the presence of destabilized microtubules, which give
structural support to cells and are involved in the movement of
genetic material during cell division. When microtubules become
destabilized, a complex process ensues which leads to the
excessive TGF-beta pathway activation, and consequent
accumulation of collagen, the primary component of fibrotic
tissue.

"We've learned in our previous studies that the treatment of
individual cells with paclitaxel helps stabilize microtubules,
thereby blocking the excessive activity of TGF-beta," Dong
explained. "So in our latest studies, we were interested in
determining whether or not paclitaxel would have any effect on
tissue with scleroderma."

For their experiments, the Duke team used mice bred to have
no immune system. They transplanted skin samples from humans
with and without scleroderma onto the backs of these mice. Some
of the skin samples were pre-treated for 30 minutes with
paclitaxel.

"We found that the skin samples from scleroderma patients
that were pre-treated with paclitaxel prior to transplantation
significantly suppressed the activity of TGF-beta and lessened
the formation of fibrotic tissue," Dong said.

Just as importantly, the researchers said, the mice that
received the skin samples from scleroderma patients exhibited
the beginning of new blood vessel formation, a process known as
angiogenesis. These new blood vessels were of mouse, and not
human, origin. Not only that, the researchers found that the
level of angiogenesis in scleroderma skin samples was twice
that of skin samples taken from patients without the disease,
regardless of whether or not they were pre-treated with
paclitaxel.

This finding of enhanced angiogenesis in scleroderma skin
samples is important for two reasons, the researchers said.

First, one of the known side effects seen in cancer patients
who take paclitaxel at much higher doses is an unwanted
amplification of fibrosis and anti-angiogenesis. Since these
two processes were not seen at the much lower doses of
paclitaxel used in these experiments, the researchers are
encouraged that paclitaxel might be safely used to benefit
patients with scleroderma. Further studies are needed to
determine optimum dosing, they said.

"Secondly, and just as importantly for our understanding of
the disease, it appears that scleroderma skin still has the
ability to send signals for repair, which includes the
formation of new blood vessels, but for whatever reason, that
repair does not occur in the patients, which it did occur in
mice," Goldschmidt said.

Goldschmidt believes that mammals, including humans, have an
inherent ability to repair damage to tissues. Specifically,
according to Goldschmidt, specialized cells in the bone marrow
known as vascular progenitor cells can be summoned to the site
of blood vessel damage and contribute to the appropriate
repairs. In scleroderma patients, this balance between damage
and repair is skewed toward damage, with patients' smaller
vessels slowly being destroyed and replaced by fibrotic
tissue.

Going into the experiments, the researchers hypothesized
that there were three possibilities to explain why the skin of
scleroderma patients cannot trigger an angiogenic response: the
skin is unable to send signals to the bone marrow; the signals
are present but for some reason the bone marrow cannot respond;
or lastly, the skin sends the signal to the bone marrow, which
produces progenitor cells, but the immune system destroys the
cells before they reach the site of damage.

"The results of this study rules out the first hypothesis,
since the skin was clearly able to send the signal for
angiogenesis, which did occur" Goldschmidt said. "The next step
is to try to further define the underlying mechanism for the
lack of blood vessels."

The researchers said that the answer is probably a
combination of the last two factors.

"After the repeated vascular injury suffered by patients
with scleroderma, it could be that the supply of progenitor
cells becomes exhausted or that the produced cells are
incompetent" Dong said. "Or, it could be that once the
progenitor cells do leave the bone marrow, they are continually
exposed to a noxious environment in the form of auto-antibodies
so that they are unable to form new blood vessels."

Other members of the research team are, from Duke, Xialin
Liu, Shoukang Zhu, and Tao Wang, as well as Laura Hummers and
Frederick Wigley, Johns Hopkins University.

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