The Regulation and Essential Functions of Matrix Metalloproteinases during Wound Healing
Stevens, Laura Jeanette
Wound healing, an essential function to the survival of all multicellular organisms, requires the precise orchestration of multiple cell types in order to repair the damaged tissue. Wound healing involves three overlapping phases: inflammation, re-epithelialization, and scar formation. Matrix metalloproteinases (MMPs) are endopeptidases of the metzincin family, which have been shown to function throughout wound healing, but their precise functions and regulatory mechanisms are unclear <em>in vivo</em> largely due to the complications of redundancy. In mammals there are 24 MMPs (seventeen secreted type MMPs and seven membrane-anchored type MMPs). MMPs are inhibited by Tissue Inhibitors of Metalloproteinases (TIMP), of which there are four in mammals. To bypass the complications of redundancy, we utilized <em>Drosophila melanogaster</em> as a model system to study MMPs <em>in vivo</em> during wound healing. <em>Drosophila</em> serve as a simple system to not only study wound healing, but the <em>Drosophila</em> genome encodes only two MMPs, one secreted (<em>Mmp1</em>) and one membrane-anchored (<em>Mmp2</em>), providing a system to elucidate the functions of each MMP class <em>in vivo</em>. Our results indicate that <em>Mmp1</em> and <em>Mmp2</em>, as well as the inhibitor, <em>Timp</em> are required for re-epithelialization, where they may function together to promote cell migration. During re-epithelialization, <em>Mmp1</em>, under the control of the JNK signaling pathway, functions to promote cell migration by facilitating collagen IV remodeling, promoting actin cytoskeleton reorganization, and inducing RTK signaling. <em>Mmp1</em> from the hemocytes may function to limit the area of both JNK and RTK signaling to the immediate vicinity of the wound. Preliminary results suggest that <em>Mmp1</em> and <em>Mmp2</em> may regulate hemostasis and the melanization cascade, as we observe both clotting and melanization defects in <em>Mmp1</em> and <em>Mmp2</em> mutants. In unwounded tissue, both <em>Mmp1</em> and <em>Timp</em> are required for basement membrane maintenance, a function they do not share with <em>Mmp2</em>. The combination of both shared and independent phenotypes between <em>Mmp1</em>, <em>Mmp2</em>, and <em>Timp</em> mutants suggest that Mmp1, Mmp2, and Timp may form a complex to promote wound healing; however, if such a complex does form in vivo it is context-specific.