NS-398, a cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis

Am J Pathol. 2005 Oct;167(4):1105-17. doi: 10.1016/S0002-9440(10)61199-6.


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-beta1, which corresponded with increased fibrosis. In addition, transforming growth factor-beta1 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / metabolism
  • Blotting, Western
  • Cell Culture Techniques
  • Cell Differentiation / drug effects
  • Cell Extracts / pharmacology
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Collagen / analysis
  • Collagen / metabolism
  • Cyclooxygenase 2 Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibrosis / chemically induced*
  • Flow Cytometry
  • Fluorescein
  • Fluorescein-5-isothiocyanate
  • Fluorescent Antibody Technique, Direct
  • Fluorescent Dyes
  • Immunohistochemistry
  • Indoles
  • Kinetics
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Models, Anatomic
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / injuries*
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiopathology*
  • Myostatin
  • Nitrobenzenes / pharmacology*
  • Regeneration / drug effects*
  • Staining and Labeling
  • Stem Cells / cytology
  • Sulfonamides / pharmacology*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta1
  • Wound Healing / drug effects


  • Antibodies, Monoclonal
  • Cell Extracts
  • Cyclooxygenase 2 Inhibitors
  • Fluorescent Dyes
  • Indoles
  • Mstn protein, mouse
  • Myostatin
  • Nitrobenzenes
  • Sulfonamides
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • DAPI
  • Collagen
  • Fluorescein-5-isothiocyanate
  • Fluorescein