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FASEB J. 2015 Mar;29(3):960-72. doi: 10.1096/fj.14-259689. Epub 2014 Nov 20.

Functional MMP-10 is required for efficient tissue repair after experimental hind limb ischemia.

Author information

1
*Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, and Cell Therapy Area, Division of Cancer, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Vascular Surgery, Complejo Hopitalario de Navarra, Pamplona, Spain; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium; and Small Animal Imaging Research Unit, CIMA and Clínica Universidad de Navarra, Pamplona, Spain.
2
*Laboratory of Atherothrombosis, Division of Cardiovascular Sciences, and Cell Therapy Area, Division of Cancer, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Vascular Surgery, Complejo Hopitalario de Navarra, Pamplona, Spain; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium; and Small Animal Imaging Research Unit, CIMA and Clínica Universidad de Navarra, Pamplona, Spain japaramo@unav.es croncalm@unav.es.

Abstract

We studied the role of matrix metalloproteinase-10 (MMP-10) during skeletal muscle repair after ischemia using a model of femoral artery excision in wild-type (WT) and MMP-10 deficient (Mmp10(-/-)) mice. Functional changes were analyzed by small animal positron emission tomography and tissue morphology by immunohistochemistry. Gene expression and protein analysis were used to study the molecular mechanisms governed by MMP-10 in hypoxia. Early after ischemia, MMP-10 deficiency resulted in delayed tissue reperfusion (10%, P < 0.01) and in increased necrosis (2-fold, P < 0.01), neutrophil (4-fold, P < 0.01), and macrophage (1.5-fold, P < 0.01) infiltration. These differences at early time points resulted in delayed myotube regeneration in Mmp10(-/-) soleus at later stages (regenerating myofibers: 30 ± 9% WT vs. 68 ± 10% Mmp10(-/-), P < 0.01). The injection of MMP-10 into Mmp10(-/-) mice rescued the observed phenotype. A molecular analysis revealed higher levels of Cxcl1 mRNA (10-fold, P < 0.05) and protein (30%) in the ischemic Mmp10(-/-) muscle resulting from a lack of transcriptional inhibition by MMP-10. This was further confirmed using siRNA against MMP-10 in vivo. Our results demonstrate an important role of MMP-10 for proper muscle repair after ischemia, and suggest that chemokine regulation such as Cxcl1 by MMP-10 is involved in muscle regeneration.

KEYWORDS:

hypoxia; inflammation; matrix metalloproteinase; regeneration

PMID:
25414484
DOI:
10.1096/fj.14-259689
[Indexed for MEDLINE]

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