title: NS-398, a cyclooxygenase-2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis.
abstract: 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.
authors.affiliation: Departments of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Shen
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: James
authors.initials: J
authors.lastname: Cummins
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects; D002457:Cell Extracts / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005355:Fibrosis / Q000139:chemically induced*; D005434:Flow Cytometry; D019793:Fluorescein; D016650:Fluorescein-5-isothiocyanate; D019085:Fluorescent Antibody Technique, Direct; D005456:Fluorescent Dyes; D007150:Immunohistochemistry; D007211:Indoles; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008953:Models, Anatomic; D018482:Muscle, Skeletal / Q000166:cytology / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology*; D055435:Myostatin; D009578:Nitrobenzenes / Q000494:pharmacology*; D012038:Regeneration / Q000187:drug effects*; D013194:Staining and Labeling; D013234:Stem Cells / Q000166:cytology; D013449:Sulfonamides / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D002457:Cell Extracts; D052246:Cyclooxygenase 2 Inhibitors; D005456:Fluorescent Dyes; D007211:Indoles; C525912:Mstn protein, mouse; D055435:Myostatin; D009578:Nitrobenzenes; D013449:Sulfonamides; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C007293:DAPI; D003094:Collagen; D016650:Fluorescein-5-isothiocyanate; D019793:Fluorescein