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(American Journal of Pathology. 2005;167:1105-1117.)
© 2005 American Society for Investigative Pathology

NS-398, a Cyclooxygenase-2-Specific Inhibitor, Delays Skeletal Muscle Healing by Decreasing Regeneration and Promoting Fibrosis

Wei Shen*{dagger}, Yong Li{dagger}{ddagger}, Ying Tang{dagger}, James Cummins{dagger} and Johnny Huard*{dagger}{ddagger}

From the Departments of Bioengineering* and Orthopaedic Surgery,{ddagger} University of Pittsburgh, Pittsburgh; and the Growth and Development Laboratory,{dagger} Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania

Nonsteroidal anti-inflammatory drugs are often prescribed after muscle injury. However, the effect of nonsteroidal anti-inflammatory drugs on muscle healing remains primarily controversial. To further examine the validity of using these drugs after muscle injury, we investigated the working mechanism of NS-398, a cyclooxygenase-2-specific inhibitor. In vitro experiments showed that NS-398 inhibited the proliferation and maturation of differentiated myogenic precursor cells, suggesting a detrimental effect on skeletal muscle healing. Using a mouse laceration model, we analyzed the in vivo effect of NS-398 on skeletal muscle healing at time points up to 4 weeks after injury. The in vivo results revealed delayed muscle regeneration at early time points after injury in the NS-398-treated mice. Compared to controls, lacerated muscles treated with NS-398 expressed higher levels of transforming growth factor-ß1, which corresponded with increased fibrosis. In addition, transforming growth factor-ß1 co-localized with myostatin, a negative regulator of skeletal muscle growth. We also found reduced neutrophil and macrophage infiltration in treated muscles, indicating that the delayed skeletal muscle healing observed after NS-398 treatment could be influenced by the anti-inflammatory effect of NS-398. Our findings suggest that the use of cyclooxygenase-2-specific inhibitors to treat skeletal muscle injuries warrants caution because they may interfere with muscle healing.




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