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Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: the role of PGE₂ and PGF₂

¹Growth and Development Laboratory, Children's Hospital of Pittsburgh, Departments of ²Orthopaedic Surgery, Molecular Genetics and Biochemistry, and ³Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania

Submitted 19 October 2005 ; accepted in final form 9 June 2006

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat skeletal muscle injury. However, studies have shown that NSAIDs may be detrimental to the healing process. Mediated by prostaglandin F₂ (PGF₂) and prostaglandin E₂ (PGE₂), the cycloxygenase-2 (COX-2) pathway plays an important role in muscle healing. We hypothesize that the COX-2 pathway is important for the fusion of muscle cells and the regeneration of injured muscle. For the in vitro experiments, we isolated myogenic precursor cells from wild-type (Wt) and COX-2 gene-deficient (COX-2^–/–) mice and examined the effect of PGE₂ and PGF₂ on cell fusion. For the in vivo experiments, we created laceration injury on the tibialis anterior (TA) muscles of Wt and COX-2^–/– mice. Five and 14 days after injury, we examined the TA muscles histologically and functionally. We found that the secondary fusion between nascent myotubes and myogenic precursor cells isolated from COX-2^–/– mice was severely compromised compared with that of Wt controls but was restored by the addition of PGF₂ or, to a lesser extent, PGE₂ to the culture. Histological and functional assessments of the TA muscles in COX-2^–/– mice revealed decreased regeneration relative to that observed in the Wt mice. The findings reported here demonstrate that the COX-2 pathway plays an important role in muscle healing and that prostaglandins are key mediators of the COX-2 pathway. It suggests that the decision to use NSAIDs to treat muscle injuries warrants critical evaluation because NSAIDs might impair muscle healing by inhibiting the fusion of myogenic precursor cells.

muscle injury; inflammation; nonsteroidal anti-inflammatory drugs; prostaglandin F₂; prostaglandin E₂; fusion

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