Matrix Metalloproteinase Inhibition Enhances the Rate of Nerve Regeneration in Vivo by Promoting Dedifferentiation and Mitosis of Supporting Schwann Cells

After peripheral nerve injury, Schwann cells (SCs) vigorously divide to survive and produce a sufficient number of cells to accompany regenerating axons. Matrix metalloproteinases (MMPs) have emerged as modulators of SC signaling and mitosis. Using a 5-bromo-2-deoxyuridine (BrdU) incorporation assay, we previously found that a broad-spectrum MMP inhibitor (MMPi), GM6001 (or ilomastat), enhanced division of cultured primary SCs. Here, we tested the hypothesis that the ability of MMPi to stimulate SC mitosis may advance nerve regeneration in vivo. GM6001 administration immediately after rat sciatic nerve crush and daily thereafter produced increased nerve regeneration as determined by nerve pinch test and growth-associated protein 43 expression. The MMPi promoted endoneurial BrdU incorporation relative to vehicle control. The dividing cells were mainly SCs and were associated with growth-associated protein 43-positive regenerating axons. After MMP inhibition, myelin basic protein mRNA expression (determined by Taqman real-time quantitative polymerase chain reaction) and active mitosis of myelin-forming SCs were reduced, indicating that MMPs may suppress their dedifferentiation preceding mitosis. Intrasciatic injection of mitomycin,the inhibitor of SC mitosis, suppressed nerve regrowth, which was reversed by MMPi, suggesting that its effect on axonal growth promotion depends on its promitogenic action in SCs. These studies establish novel roles for MMPs in peripheral nerve repair via control of SC mitosis, differentiation, and myelin protein mRNA expression.