Collagenase-3 (MMP-13) Enhances Remodeling of Three-Dimensional Collagen and Promotes Survival of Human Skin Fibroblasts

Abstract

Collagenase-3 (MMP-13) is a matrix metalloproteinase capable of cleaving a multitude of extracellular matrix proteins in addition to fibrillar collagens. Human MMP-13 is expressed by fibroblasts in chronic cutaneous ulcers, but not in normally healing adult skin wounds. However, MMP-13 is produced by fibroblasts in adult gingival and in fetal skin wounds characterized by rapid collagen remodeling and scarless healing. Here, we have examined the role of human MMP-13 in remodeling of three-dimensional (3D) collagenous matrix by primary adult human skin fibroblasts. The high level of human MMP-13 expression by fibroblasts achieved by adenoviral gene delivery resulted in potent enhancement of remodeling and contraction of 3D collagen. Fibroblasts expressing MMP-13 in 3D collagen possessed altered filamentous actin morphology with patch-like actin distribution in cell extensions. The expression of MMP-13 promotes survival and proliferation of fibroblasts in floating collagen gel, and results in activation of Akt and extracellular signal-regulated kinase-1/2 by these cells. The results provide evidence for a novel role for human MMP-13 in regulating dermal fibroblast survival, proliferation, and interaction in 3D collagen, which may be an important survival mechanism for fibroblasts in chronic skin ulcers and contribute to scarless healing of adult gingival and fetal skin wounds.

In Vivo Interstitial Migration of Primitive Macrophages Mediated by JNK-Matrix Metalloproteinase 13 Signaling in Response to Acute Injury

“…Using this assay, we demonstrate that the JNK molecule, but not ERK or p38 MAPK, is a critical factor mediating primitive macrophage migration in vivo. Activation of ERK1/2 and p38 MAPK secondary to Mmp13 activation in human fibroblasts (50) and mouse macrophages (43) may be important for macrophage proliferation, survival, and cytokine production, as previously reported, but do not appear to be required for chemotactic migration of primitive macrophages.…”

Distinct biological events generated by ECM proteolysis by two homologous collagenases

“…Overall, the remodeling events of collagenrich ECM by either MMP-1 or MMP-13 contributed to fibroblastmatrix communication, suggesting that such stimulation may be involved in cell migration in normal and pathological processes. For example, MMP-13 has been shown to enhance the remodeling of 3D collagen matrix, to affect cell morphology, and to promote proliferation of dermal fibroblasts in both in vitro and in vivo models of wound healing (44,55).…”

Transforming growth factor‐β signaling in cancer invasion and metastasis

“…In addition, expression of MMP-13 can promote survival of both SCC cells and stromal fibroblasts. 63,64 Invasion of head and neck SCC cells is potently stimulated by TGF-b and this is mediated via p38 MAPK pathway. 60 Interestingly, the predominant p38 isoforms expressed by head and neck SCC cells are p38a and p38d, both of which regulate invasion capacity and growth of head and neck SCC cells in culture and in vivo, suggesting these p38 isoforms as potential therapeutic targets in head and neck SCC.…”