Collagen of Chronically Inflamed Skin Is Over-Modified and Upregulates Secretion of Matrix Metalloproteinase 2 and Matrix-Degrading Enzymes by Endothelial Cells and Fibroblasts

Abstract

In order to investigate the properties of collagen in chronically inflamed tissue, we isolated collagen from the ear skin of mice with chronic contact dermatitis and examined its biochemical characteristics and the functions that regulate the secretion of matrix metalloproteinase 2 and collagen-degrading enzymes from endothelial cells and fibroblasts. Collagen in skin with chronic contact dermatitis comprised 60% type I collagen and 40% type III collagen, which latter is higher than the content of type III collagen in control skin (35%). The denaturation temperature was higher (42 degrees C) than that of control skin (39 degrees C). The alpha2 chain of type I collagen was over-hydroxylated at both proline and lysine residues. Segment-long-spacing crystallites of type I collagen were unusually connected in tandem. Collagen of chronically inflamed skin was less susceptible to matrix metalloproteinase 2 after heat denaturation. Endothelial cells and fibroblasts secreted an increased amount of matrix metalloproteinase 2 when cultured on a gel formed from the collagen of chronically inflamed skin. Collagen-degrading activity secreted from fibroblasts was also upregulated when cells were in contact with collagen of chronically inflamed skin. These results suggest that the collagen in chronically inflamed tissue has altered biochemical characteristics and functions, which may affect the pathogenesis of the chronic skin disease.

Hypertrophic Scar Cells Fail to Undergo a Form of Apoptosis Specific to Contractile Collagen—The Role of Tissue Transglutaminase

“…In addition, HTS cell modification of collagen causes resistance to enzymatic cleavage by MMP-2, a collagenase highly active during cutaneous wound healing. These results are analogous to recent findings in a model of chronic dermatitis induced in rabbit ears (Hirota et al, 2003) and are of particular interest considering work by Buckley et al (1999), who implicated potential breakdown products of the ECM in the initiation of apoptosis in both lymphocytic cells and fibroblasts. Small soluble peptides containing the RGD amino acid motif were reported to directly induce apoptosis through an integrinindependent mechanism by direct binding to and activation of pro-caspase-3 as apposed to the alternative mechanism of inducing apoptosis (termed anoikis) through blocking integrin-mediated cell-matrix contact (Frisch and Ruoslahti, 1997).…”

“…We further postulated that this phenomenon of apoptotic resistance might be caused by the matrix of HTS being overmodified in some way, either via intracellular posttranslational modification that goes on during biosynthesis or through extracellular biochemical modification, since chronic fibrotic tissue (both skin and liver) is known to be excessively cross-linked (Ricard-Blum et al, 1993, 1996Dolynchuk, 1996;Hirota et al, 2003). Overmodification of ECM would considerably change its biochemical properties and how cells interact with it, potentially affecting the mechanical properties of the matrix and thus the tensional load put upon the inhabiting cells.…”

“…We further investigated whether the differences in apoptosis ability under these specific circumstances were related to changes in biochemical modification of collagen, since chronic fibrosis is linked with overmodification of the ECM in both the liver and skin (Ricard-Blum et al, 1993, 1996Hirota et al, 2003) and an increased isopeptide cross-linking of ECM has been reported in HTS tissue (Dolynchuk, 1996). Overmodification of ECM proteins can dramatically alter the behavior of cells inhabiting the matrix through changes in mechanical properties, changes in the availability of a variety of biologically active substances by binding to the ECM or the availability of specific binding motifs within the matrix molecules themselves, and finally altering the breakdown and remodelling of the matrix.…”

Analysis of skin patch test results and metalloproteinase-2 levels in a patient with contact dermatitis

“…ACD involves deformation of cutis and epidermis texture as well as remodeling of collagen fibre streaks. An increased amount of type I and type III collagen has been demonstrated in the skin affected by chronic contact dermatitis [ 28 ]. Fibroblasts are among potential targets of MMP-2.…”

Directing stem cells into the keratinocyte lineage in vitro

“…In addition to its structural role, skin ECM plays a physiological role, by influencing the immediate microenvironment of the cells embedded within it. Histological studies have reported extensive remodeling of skin ECM during growth and development (120) as well as under various pathological conditions (121,122,123).…”