Jefferson scientists show inhibiting specific enzyme may lead to therapy for scleroderma

October 25, 2000

Blocking the action of a specific enzyme may someday prove to be an effective treatment for scleroderma, a potentially life-threatening disease that results in the overproduction of collagen and which can affect the skin, joints and multiple internal organs.

Researchers at Jefferson Medical College, in collaboration with scientists at the University of Pennsylvania, have shown in the laboratory that the drug rottlerin appears to decrease the activity of a protein that affects the expression of a collagen-producing gene.

"It appears we have uncovered a novel enzymatic pathway involved in the regulation of collagen gene expression in normal and scleroderma cells," says Sergio Jimenez, M.D., Dorrance H. Hamilton Professor of Medicine and professor of biochemistry and molecular pharmacology at Jefferson Medical College of Thomas Jefferson University in Philadelphia.

"More importantly, there is a possibility of affecting this pathway with therapeutic compounds that may be useful in treating the disease." Dr. Jimenez reports his team's findings October 30 at the annual meeting of the American College of Rheumatology in Philadelphia.

Some 300,000 Americans have scleroderma, which is actually categorized as two main diseases: localized scleroderma and systemic sclerosis. The former affects only the skin. Systemic sclerosis can affect the internal organs, skin and the body's small blood vessels. Scleroderma can be devastating; some aggressive forms of the disease can result in death after only a few months.

In scleroderma, the immune system interacts with the body's blood vessels and fibroblasts, cells that produce collagen, resulting in an excess of collagen. No one understands exactly how, but these events lead to the hallmarks of scleroderma: thickened skin and damage to vessels and internal organs.

In scleroderma, collagen-producing genes go into overdrive and affected cells produce two to three times more collagen than normal. Dr. Jimenez and his colleagues had previously uncovered a new and unexpected biochemical "cascade" involved in the expression of normal collagen-producing genes and wanted to see whether the pathway was also involved in controlling collagen gene expression in scleroderma cells.

The researchers took advantage of a specific substance that blocked key parts of this biochemical cascade to see how they may be involved in scleroderma. They used the drug rottlerin, which specifically blocks the activity of the enzyme, protein kinase C delta, which is involved in important metabolic processes.

"When we used rottlerin to inhibit protein kinase C delta and examined its effects on collagen production by normal and scleroderma cells, we found the compound blocked the collagen gene expression by 90 percent or more in both types of cells," Dr. Jimenez explains.

"Rottlerin abolished the increased activity of the collagen gene and reduced its expression. Protein expression was also down-regulated 80 to 90 percent, and collagen biosynthesis was down-regulated as well," Dr. Jimenez says.

How might this be used in humans? According to Dr. Jimenez, rottlerin may be administered in a tablet form "in relatively low doses, which could be expected to reduce the expression of the collagen gene.

Since the gene expression is so much higher in scleroderma, you would expect the effect to be more pronounced on scleroderma cells than on normal cells.

"The next step would be to attempt to confirm in an animal model what we've shown in the laboratory," Dr. Jimenez says. "There are mouse models that mimic forms of scleroderma, some of which display the exaggerated forms of collagen formation."

While "understanding the molecular events involved in the pathogenesis of scleroderma is paramount" to finding effective treatments, Dr. Jimenez notes that many genes play various unknown roles in the disease. At the same time, he says, "In contrast to many complex diseases, we think that there is more likely an environmental trigger setting off genetic changes leading to the disease."
Editor's Note: Dr. Sergio Jimenez will present "Protein Kinase C d Regulation of Type 1 Collagen Gene Expression in Normal and Systemic Sclerosis (Scleroderma) Fibroblasts," at the American College of Rheumatology meeting during an ACR Mini-Symposium in Room 204A in the Pennsylvania Convention Center beginning at 2:15 p.m. on Monday, Oct. 30.

Thomas Jefferson University

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