Restylane stimulates collagen production

Senior investigator John J. Voorhees, M.D., tells Dermatology Times the mechanical stretching of the fibroblast appears to stimulate the genes of fibroblasts to produce more collagen and to decrease production of collagenase, the enzyme that degrades collagen. But stretching may not be the entire explanation.

Fibroblast role

"Over the last five years we have shown that a fundamental problem in aging skin, as well as photoaging, is that the collagen becomes increasingly broken up.

"We realized the importance of this when we took the fibroblasts out of photoaged skin and put them on nonbroken collagen. They made just as much collagen as fibroblasts from photoprotected skin. So, basically, the fibroblast is okay, it is not just a problem of photoaging."

Dr. Voorhees hypothesizes, "If we could restretch the collapsed fibroblast and make it look like a young fibroblast, maybe it would reacquire the functional activity of the photoprotected fibroblasts, i.e., the production of more collagen. And that is exactly what happened.

"Everybody thought that fillers work by virtue of their physical presence, filling in holes, nooks and crannies. I don't doubt that is true for a few weeks" before the filler is degraded and absorbed, he says.

However, in a pilot study that is included in the Materials and Methods section of the study, four of six subjects showed an increase in pro-collagen messenger RNA at one week.

"The hyaluronic acid filler is absorbed; it got smaller and smaller over time. Then the collagen is likely to take over and dominate the clinical effect," Dr. Voorhees says.

In vitro work has established that stretching a variety of cell types initiates a signal from the membrane to the nucleus and stimulates gene expression.

"In this instance, we measured increased expression of genes for collagen, TIMP, and growth factor TGF-B. The stretch caused these things to happen," he says.

Dr. Voorhees says researchers used Restylane because, at the time the study was planned, it was the only commercially available product with a long safety record. Medicis donated product for the trial but played no other role and "did not see the article until it was published," he says. Funding came from the department of dermatology Human Appearance Research Fund.

Dr. Voorhees is cautious about extending these findings to other fillers and even to other formulations of hyaluronic acid. He does not have access to proprietary information on products, but assumes that differences in cross-linking "is probably the basis of their patents. You would expect that the different cross-linking would alter the biophysical properties of the cross-linked hyaluronic molecule into somewhat of a different shape.