HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bryer, S. C. Articles by Koh, T. J. Search for Related Content PubMed PubMed Citation Articles by Bryer, S. C. Articles by Koh, T. J.

Urokinase-Type Plasminogen Activator Plays Essential Roles in Macrophage Chemotaxis and Skeletal Muscle Regeneration¹

Scott C. Bryer^*, Giamila Fantuzzi, Nico Van Rooijen and Timothy J. Koh^2,*

^* Department of Movement Sciences, and Department of Human Nutrition, University of Illinois, Chicago, IL 60612; and Department of Molecular Cell Biology, Vrije University, Amsterdam, The Netherlands

Although macrophages are thought to play important roles in tissue repair, the molecular mechanisms involved remain to be elucidated. Mice deficient in urokinase-type plasminogen activator (uPA^–/–) exhibit decreased accumulation of macrophages following muscle injury and severely impaired muscle regeneration. We tested whether macrophage-derived uPA plays essential roles in macrophage chemotaxis and skeletal muscle regeneration. Macrophage uPA was required for chemotaxis, even when invasion through matrix was not necessary. The mechanism by which macrophage uPA promoted chemotaxis was independent of receptor binding but appeared to depend on proteolytic activity. Exogenous uPA restored chemotaxis to uPA^–/– macrophages and rescued muscle regeneration in uPA^–/– mice. Macrophage depletion in wild-type (WT) mice using clodronate liposomes resulted in impaired muscle regeneration, confirming that macrophages are required for efficient healing. Furthermore, transfer of WT bone marrow cells to uPA^–/– mice restored macrophage accumulation and muscle regeneration. In this rescue, transferred WT cells appeared to contribute to IGF-1 expression but did not fuse to regenerating fibers. These data indicate that WT leukocytes, including macrophages, that express uPA were sufficient to rescue muscle regeneration in uPA^–/– mice. Overall, the results indicate that uPA plays a fundamental role in macrophage chemotaxis and that macrophage-derived uPA promotes efficient muscle regeneration.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by United States Army Medical Research and Materiel Command Grant W81XWH-05-1-0159 (to T.J.K.). S.C.B. was supported by the National Aeronautics and Space Administration Graduate Student Research Program Grant NNG04GN53H.

² Address correspondence and reprint requests to Dr. Timothy J. Koh, Department of Movement Sciences, University of Illinois, 1919 West Taylor Street, m/c 994, Room 529, Chicago, IL 60612. E-mail address: tjkoh{at}uic.edu

³ Abbreviations used in this paper: uPA, urokinase-type plasminogen activator; WT, wild type; BMDMs, BM-derived macrophages; EDL, extensor digitorum longus; TA, tibialis anterior; BM, bone marrow; MyoD, myogenic regulatory factor; HGF, hepatocyte growth factor; iNOS, inducible NO synthase; uPA^–/–-mx, uPA^–/– muscle extract.

This article has been cited by other articles:

				M. Cheng, M.-H. Nguyen, G. Fantuzzi, and T. J. Koh Endogenous interferon-{gamma} is required for efficient skeletal muscle regeneration Am J Physiol Cell Physiol, May 1, 2008; 294(5): C1183 - C1191. [Abstract] [Full Text] [PDF]