Mice that lack matrix metalloproteinase-9 display delayed wound healing associated with delayed reepithelization and disordered collagen fibrillogenesis

Abstract

Matrix metalloproteinase- (MMP-9) is involved in processes that occur during cutaneous wound healing such as inflammation, matrix remodeling, and epithelialization, To investigate its role in healing, full thickness skin wounds were made in the dorsal region of MMP-9-null and control mice and harvested up to 14 days post wounding. Gross examination and histological and immunohistochemical analysis indicated delayed healing in MMP-9-null mice. Specifically, MMP-9-null wounds displayed compromised reepithelialization and reduced clearance of fibrin clots. In addition, they exhibited abnormal matrix deposition, as evidenced by the irregular alignment of immature collagen fibers. Despite the presence of matrix abnormalities, MMP-9-null wounds displayed normal tensile strength. Ultrastructural analysis of wounds revealed the presence of large collagen fibrils, some with irregular shape. Keratinocyte proliferation, inflammation, and angiogenesis were found to be normal in MMP-9-null wounds. In addition, VEGF levels were similar in control and MMP-9-null wound extracts. To investigate the importance of MMP-9 in wound reepithelialization we tested human and murine keratinocytes in a wound migration assay and found that antibody-based blockade of MMP-9 function or MMP-9 deficiency retarded migration. Collectively, our observations reveal defective healing in MMP-9-null mice and suggest that MMP-9 is required for normal progression of wound closure.

Neutrophils and Wound Repair: Positive Actions and Negative Reactions

“…37 MMP-9, on the other hand, is expressed at the advancing front of the wound epithelium 39 and findings from animal studies evaluating the importance of MMP-9 in wound healing have varied. In MMP-9 knockout mice, accelerated closure of both corneal and skin wounds was reported by Mohan et al, 39 while a delay in re-epithelialization and collagen organization was described by Kyriakides et al 40 In another study, Reiss et al showed that treatment of wounds with active MMP-9 alters the structure of the collagen IV-containing basement membrane and delays reepithelialization. 41 Like MMP-2, abundant active MMP-9 is associated with chronic wounds.…”

Differential Ly6C Expression after Renal Ischemia-Reperfusion Identifies Unique Macrophage Populations

“…Mmp8 contributes to the resolution of inflammation, 44 while Mmp9 regulates re-epithelialization and collagen fibril formation during wound repair. 45 Chi3l1 encodes a protein secreted by macrophages that mediates kidney repair by limiting tubular cell death, 46 which may explain the increased cell death with c-fms inhibitor treatment. Collectively, these data clearly indicate the Ly6C int subset plays a paracrine role in repair of the tubular epithelium.…”

Integration of Blood Outgrowth Endothelial Cells in Dermal Fibroblast Sheets Promotes Full Thickness Wound Healing

“…They did however produce PDGF-BB, although there is no consensus on whether this factor improves collagen organization [50,51]. Perhaps, MMP-9 expression by hBOEC contributed to collagen organization, since a lack of this MMP results in disordered fibrillogenesis [52]. hBOEC abundantly produce PlGF.…”