title: Functional MMP-10 is required for efficient tissue repair after experimental hind limb ischemia.
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.
authors.affiliation: *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.
authors.forename: Violeta
authors.initials: V
authors.lastname: Gomez-Rodriguez
authors.affiliation: *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.
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
authors.affiliation: *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.
authors.forename: Esther
authors.initials: E
authors.lastname: Martinez-Aguilar
authors.affiliation: *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.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rodriguez
authors.affiliation: *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.
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Fernandez-Alonso
authors.affiliation: *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.
authors.forename: Jens
authors.initials: J
authors.lastname: Serneels
authors.affiliation: *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.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bobadilla
authors.affiliation: *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.
authors.forename: Ana
authors.initials: A
authors.lastname: Perez-Ruiz
authors.affiliation: *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.
authors.forename: Maria
authors.initials: M
authors.lastname: Collantes
authors.affiliation: *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.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mazzone
authors.affiliation: *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.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Paramo
authors.affiliation: *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.
authors.forename: Carmen
authors.initials: C
authors.lastname: Roncal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054360:Chemokine CXCL1 / Q000378:metabolism; D004195:Disease Models, Animal; D004546:Elapid Venoms / Q000633:toxicity; D006614:Hindlimb / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D007511:Ischemia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009135:Muscular Diseases / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity; D012038:Regeneration; D015427:Reperfusion Injury / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D014945:Wound Healing / Q000502:physiology*
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D004546:Elapid Venoms; D009498:Neurotoxins; C005082:notexin; D053506:Matrix Metalloproteinase 10
keywords: hypoxia; inflammation; matrix metalloproteinase; regeneration