Discovery by U of A researchers raises prospect that we’ll turn off the processes that lead to disfiguring scars caused by burns, serious wounds

A recent discovery by a team of University of Alberta researchers has raised the intriguing prospect that clinicians will one day be able to mediate or even turn off the biological processes that lead to disfiguring scars caused by burns and serious wounds.

Aziz Ghahary, a professor in the Departments of Surgery and Medicine, and his collaborators have made a stunning discovery—essentially finding a protein that’s implicated in how the healing process ends. "After five years of a tedious searching for a matrix metalloproteinase-1 (MMP-1) stimulating factor, we identified and characterized a protein with strong MMP-1 stimulating effects on skin cells," he explains. "This protein is now referred as keratinocyte-derived anti-fibrogenic factor (KDAF)." Later studies identified this protein as a keratinocytes releasable stratifin whose extracellular functions is completely unknown. The findings for the first time suggest and emphasize the critical role of mesenchymal-epithelial cell interaction in ECM modulation in these cells.

This is important because it may identify a target in the healing process that can be used to slow down or even prevent the scarring process. Dermal fibrosis, or scarring, is caused by overproduction of extracellular matrix (ECM) proteins and lack of degradation signals. In large and severe wounds, which remain open for more than three weeks, ECM expressing cells continue to produce many ECM components such as fibronectin, type I and type III collagen until keratinocytes form the epidermal layer and cover the wound surface. Unfortunately, explains Dr. Ghahary, by that time an excessive ECM deposition within the healing tissue has done its damage and the tissue has become fibrotic, or scarred.

Recent studies showed that an imbalance in extracellular matrix (ECM) production and degradation by a large family of enzymes known as MMPs is the common hallmark of several of these complications. In spite of the fact that many studies clearly demonstrated that over-production of MMPs plays a critical role in tissue erosion seen in rheumatoid arthritis and osteoarthritis as well as the lack of new tissue formation seen in non-healing wounds, the cause of MMPs over-production at joint and wound sites and even in body fluid is not known.

While the researchers have essentially been able to reproduce the protein and prove it enhances MMP-1 that degrades collagen type I and III important in the scarring process, they now have to prove it works in animal models. From there, phase I clinical trials would follow, and, says Dr. Ghahary, if that goes well, there is a potential for helping millions of people who have suffered post-burn dermal fibrosis and serious wounds.

Dr. Ghahary and his colleagues, Edward Tredget (Surgery), Feridoun Karimi-Busheri and Michael Weinfeld (Oncology) were recently awarded operating funding of $113,154 for three years from the Canadian Institutes of Health Research to further the work.

"We think that skin cells produce at least two sets of proteins, keratinocyte derived antifibrogenic factors (DKAF) and keratinocyte-derived collagen suppressive factor (DK-CSF), whose levels control the production and degradation of the main skin molecules such as collagen by another type of skin cells know as fibroblasts."

The work has other implications: "These findings let us to believe that patients who suffer from MMPs over-expressing related diseases such as rheumatoid arthritis and osteoarthritis as well as those with nonhealing wounds would have higher levels of circulating KDAF." So, says Dr. Ghahary, the goal of the study is to explore the possible link between levels of our recently identified KDAF as a cause of overexpression of MMPs in these patients. Finding this factor in serum may, in fact, indicate the possible role of circulating KDAF in controlling ECM in other parts of the body, Dr. Ghahary explains.

Dr. Ghahary and his colleagues, Dr. Tredget (Surgery) and Walter Maksymowych (Medicine), were recently awarded IMHA High Risk operating funding of $ 60,000 for two years to explore the possible role of circulating KDAF in lMMPs overexpressing related disease such as rheumatoid arthritis and non-healing wounds. As this finding marks the first indication that a keratinocyte releasable form of stratifin may in fact function as a strong MMP-1 stimulating factor for fibroblasts, we have been able to patent it as a new anti-fibrogenic factor, he explains. The cost of patent and commercialization of this factor has recently been supported by both AHFMR and CIHR Proof of Principle funding. Thus, the present invention relates to a method for the prevention and/or treatment of fibroproliferative disorders.