ADAMTS1 Proteinase Is Up-regulated in Wounded Skin and Regulates Migration of Fibroblasts and Endothelial Cells

Abstract

The metalloproteinase ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs) is induced under inflammatory conditions, and it is also a potent inhibitor of angiogenesis. Due to these properties, we speculated about the role of ADAMTS1 in cutaneous wound repair. Here we have shown up-regulation of ADAMTS1 expression in wounds of normal and particularly of healing-impaired genetically diabetic mice. Immunofluorescence staining identified macrophages as the source of ADAMTS1 in early wounds, whereas keratinocytes and fibroblasts produce this protein at later stages of wound healing. The distribution of AD-AMTS1 in the normal and wounded epidermis, its regulation in cultured keratinocytes, as well as the skin phenotype of ADAMTS1 knock-out mice suggests a role of this metalloproteinase in keratinocyte differentiation. Furthermore, we provide evidence for a novel dual function of ADAMTS1 in fibroblast migration; although low concentrations of this protein stimulate fibroblast migration via its proteolytic activity, high concentrations inhibit this process because of binding to fibroblast growth factor-2 and subsequent inhibition of its promotogenic activity. Similar effects were also observed with endothelial cells. Taken together, our results suggest a role of ADAMTS1 in keratinocyte differentiation and migration of fibroblasts and endothelial cells in healing skin wounds.Repair of wounded tissue is a complex process that requires temporal and spatial coordination of different events, including inflammation, formation of new tissue, angiogenesis, and matrix remodeling. These processes are regulated by growth factors and cytokines but also by cell-cell and cell-matrix interactions (1-3). Proteolytic processes are required during all phases of cutaneous wound healing. Proteolysis is necessary to allow inflammatory cells to enter the wound site and to degrade the provisional fibrin clot. Proteinases are involved in cell migration, in wound contraction, and in scar remodeling, and the role of serine proteinases, such as plasmin and leukocyte elastase and of matrix metalloproteinases, in wound repair is well established (4 -6). In addition, another proteinase family has recently been identified, whose members are of potential interest for the wound-healing process based on their biological activities. These proteinases, which are designated ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) comprise a family of Zn 2ϩ -dependent metalloproteinases closely related to the matrix metalloproteinases and ADAM family of proteinases. They are structurally characterized by a metalloproteinase domain, a disintegrin-like domain, and several thrombospondin motifs (7). The adamts1 gene was originally cloned from a colon carcinoma cell line (8). Some of the ADAMTS1 substrates have been identified, and they include mainly proteoglycans, such as aggrecan (9, 10) and versican (11). adamts1 knock-out mice are characterized by growth retardation, changes in kidney structure, and impaired female fertil...

Kaempferol targets estrogen‑related receptor α and suppresses the angiogenesis of human retinal endothelial cells under high glucose conditions

“…TSP-1 deficiency has been found to exacerbate the pathogenesis of diabetic retinopathy (7). At high concentrations, ADAMTS-1 has been shown to inhibit the endothelial migration induced by combined treatment with VEGF and basic FGF (31). In the present study, it was found that kaempferol increased the expression of TSP-1 and ADAMTS-1 mRNA in HRECs under high glucose conditions.…”

ADAMTS1 Is a Unique Hypoxic Early Response Gene Expressed by Endothelial Cells

“…Many reports have shown that hypoxia is closely related to angiogenesis. In addition, ADAMTS1 has been reported to inhibit angiogenesis in a cornea pocket assay and chorioallantoic membrane assay (35); however, Krampert et al (36) reported that ADAMTS1 has dual functions (i.e. ADAMTS1 stimulated the migration of fibroblasts at low concentrations but inhibited this process at high concentrations).…”

Impaired Biomechanical Properties of Diabetic Skin

“…9,27,28 In vitro collagen matrices that were artificially glycated displayed a decrease in biomechanical properties when compared to nonglycated matrices both in vitro and when implanted in vivo. 29 There has also been a suggestion that collagen breakdown may be altered in the setting of diabetes due to glycation and cross linkage.…”