P434Functional MMP-10 is required for efficient tissue repair following experimental hindlimb ischemia

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Abstract

Purpose: Tissue ischemia triggers a bunch of cellular responses directed to restore blood flow and accelerate repair. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, contribute extensively to tissue remodeling in a variety of normal and disease processes, including ischemic disorders associated to vascular dysfunction (e.g.: peripheral artery disease, PAD). High gelatinolytic activity is necessary for tissue remodeling in response to arterial occlusion in experimental ischemia, however, the contribution of other MMPs, such as; collagenases, or stromelysins, has not yet been investigated. MMP-10 or stromelysin 2 has been suggested to be involved in disorders associated to tissue remodeling and inflammation, although it remains unknown its involvement in ischemic diseases.

Methods: we used a model of femoral artery occlusion in wild type (WT) and MMP-10 deficient (Mmp10-/-) mice to study the role of MMP-10 in skeletal muscle repair.

Results: At the degenerative phase, MMP-10 deficiency reduced tissue perfusion and increased necrosis and inflammation. At the regenerative phase, MMP-10 deficiency resulted in reduced tissue regeneration. The injection of recombinant human MMP-10 (rhMMP10) in Mmp10-/- mice rescued the observed phenotype. Compared to WT, ischemic Mmp10-/- muscles had higher levels of Cxcl1 (Gro-alpha), suggesting the involvement of chemokine production in muscle regeneration by MMP-10.

Conclusions: Our results demonstrate an important role of MMP-10 for proper muscle repair during degenerative and regenerative phases of limb ischemia, and open new pathways for specific manipulation of MMP-10 in ischemic conditions.

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