Researchers cut fibrosis formation, increase muscle strength after injury

Surgeons are on their way to blocking degeneration, controlling muscle formation, promoting regeneration and eliminating scar tissue.

Scar tissue threatens muscle function and regeneration, but physicians may prevent and even eliminate existing scar tissue using new antifibrosis agents, fewer NSAIDs and metalloproteinase-1.

New research on mice suggests that blocking transforming growth factor-ß1 may prevent the creation of scar tissue and promote muscle healing. “The release of a lot of satellite [cells] and growth factors lead to the regeneration of the muscle,” said University of Pittsburgh researcher Wei Shen, MD. “However, the release of some other molecules, for example, TGF-ß1, can lead to the formation of fibrosis.”

This research, led by Johnny Huard, PhD, also at the University of Pittsburgh, found that TGF-ß1 triggers cellular differentiation in satellite cells.

“Based on our research, we have found that these satellite cells and muscle stem cells not only differentiate to form myofibers, but they can also differentiate to form fibroblasts and myofibroblasts, which is a major cell type in the scar tissue,” Shen said during this presentation at the American Orthopaedic Society for Sports Medicine 2005 Annual Meeting.

After discovering TGF-ß1 as the key to fibrosis, the researchers identified decorin, suramin, gamma-interferon and relaxin as TGF-ß1 blockers. “By using suramin, we have shown that we can decrease fibrosis formation and increase the strength of muscle after injury,” Shen said. They noted similar reactions with the other antifibrosis agents and also found a shorter fibrosis period using gamma-interferon.

Blocking inflammation and regeneration

To relieve the inflammation that accompanies injury, physicians often administer NSAIDs. “As sports medicine doctors, we prescribe this group of drugs more than any other doctors in this country,” Shen said.

But these drugs may cause more problems than they alleviate. “These types of drugs can have an effect on the muscle healing based on our research and other research,” he said.

NSAIDs inhibit PGE2 and PGF2a, two important inflammatory mediators that influence protein production and cell fusion. PGE2 obscures fibroblast growth and blocks collagen production. PGF2a promotes the formation of mature myotubes, which are essential to tissue regeneration. “So, if we block production of these two [factor mediators] by COX-2 inhibitors, we're actually increasing the formation of scar tissue,” Shen said.

MMP-1

Since scar tissue can form in as little two weeks after severe injury, physicians often see patients after the damage is done. But injecting mice with matrix metalloproteinase-1 (MMP-1) “can actually restart the regeneration,” Shen said.

The proteinase breaks down extracellular matrix compounds and therefore, can be used to disintegrate scar tissue. “So, the MMP-1 is like a big wrecking ball to knock down this scar tissue wall and re-initiate the regeneration,” Shen said.

Incorporating these methods may enhance muscle healing during each stage of injury repair. But researchers need to conduct further animal studies before human application.

“Since we have known there are different phases of the muscle healing, we can probably do something about each phase to improve muscle healing by blocking degeneration and controlling formation, promote the regeneration [of healthy tissue] and prevent the fibrosis scar tissue,” he said.

For more information:
Li Y, Fu FH, Huard J. Current Concepts: New management strategies for muscle injury. Presented at the American Orthopaedic Society for Sports Medicine 2005 Annual Meeting. July 14-17, 2005. Keystone, Colo.