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Expression Profiling of Cytokines and Related Genes in Regenerating Skeletal Muscle after Cardiotoxin Injection: A Role for Osteopontin

https://doi.org/10.1016/S0002-9440(10)63644-9Get rights and content

To examine the roles of cytokines in muscle regeneration, we injected cardiotoxin into mouse tibialis anterior muscle and examined the expression profiles of cytokines and related genes in the regeneration process. Expression of 40, 64, and 7 genes among 522 genes spotted on a cytokine expression array were increased more than fivefold at 48 hours, 96 hours, and 7 days after toxin injection, respectively, when compared with those of the control muscle. Especially the levels of mRNA for chemokines and chemokine receptors, many of which are potent regulators of macrophages, were highly elevated 48 hours after injury. The expression of osteopontin (OPN), a versatile regulator of inflammation and tissue repair, was up-regulated more than 118-fold in regenerating muscle at 48 hours after injury. Northern blotting confirmed that the expression of OPN was highest at 48 hours after cardiotoxin injection and declined sharply thereafter. Immunohistochemistry showed that OPN was detected both in the cytoplasm of macrophages and in necrotic muscle infiltrated with macrophages. Our studies suggest OPN may serve as an adhesion molecule that promotes macrophage binding to necrotic fibers and may be an important mediator in the early phase of muscle regeneration.

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Supported by grants-in-aid for scientific research from the Center of Excellence, Research on Nervous and Mental Disorders (10B-1, 13B-1), health science research grants for research on the human genome and gene therapy (H10-genome-015, H13-genome-001), for research on brain science (H12-brain-028) from the Ministry of Health, Labor, and Welfare; grants-in aid for scientific research (10557065, 11470153, 11170264, and 14657158) from the Ministry of Education, Culture, Sports, Science, and Technology; and a research grant from the Human Frontier Science Project.

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