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

Abstract

We studied the role of matrix metallo proteinase‐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.—Gomez‐Rodriguez, V., Orbe, J., Martinez‐Aguilar, E., Rodriguez, J. A., Fernandez‐Alonso, L., Serneels, J., Bobadilla, M., Perez‐Ruiz, A., Collantes, M., Mazzone, M., Paramo, J. A., Roncal, C., Functional MMP‐10 is required for efficient tissue repair after experimental hind limb ischemia. FASEB J. 29, 960–972 (2015). www.fasebj.org