Measurement of matrix metalloproteinase 9-mediated Collagen type III degradation fragment as a marker of skin fibrosis

Abstract

BackgroundThe current study utilized a Bleomycin-induced model of skin fibrosis to investigate the neo-epitope CO3-610 (KNGETGPQGP), a fragment of collagen III released during matrix metalloproteinase-9 (MMP9) degradation of the protein, we have previously described as a novel biomarker for liver fibrosis. The aim was to investigate CO3-610 levels in another well characterised model of fibrosis, to better describe the biomarker in relation to additional fibrotic pathologies.MethodsSkin fibrosis was induced by daily injections of Bleomycin to a total of 52 female C3 H mice, while control mice (n = 28) were treated with phosphate buffered saline (PBS), for 2, 4, 6 or 8 weeks. Skin fibrosis was evaluated using Visiopharm software on Sirius-red stained skin sections. Urine ELISA assays and creatinine corrections were performed to measure CO3-610 levels.ResultsCO3-610 levels were significantly higher in Bleomycin-treated vs. PBS-treated mice at each time point of termination. The mean increases were: 59.2%, P < 0.0008, at 2 weeks; 113.5%, P < 0.001, at 4 weeks; 136.8%, P < 0.0001 at 6 weeks; 157.2%, P < 0.0001 at 8 weeks). PBS-treated mice showed a non-significant increase in CO3-610 levels (mean increase for weeks 2-8 = 1.7%, P = 0.789) CO3-610 levels assayed in urine were statistically significantly correlated with Western blot analysis showing increased skin fibrosis (P < 0.0001, r = 0.65).ConclusionIncreased levels in mouse urine of the MMP-9 mediated collagen III degradation fragment CO3-610 were correlated with skin fibrosis progression, suggesting that CO3-610 may be a potential positive biomarker to study the pathogenesis of skin fibrosis in mice.

Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis

“…In addition, CO4-MMP levels were significantly correlated with collagen deposition in the CCl 4 model of liver fibrosis. The data are in alignment data reported in other studies in these animal models, demonstrating that the presence of neoepitopes is a good biochemical marker of pathologies involving excessive ECM remodeling [21-27]. A difference in the levels of CO4-MMP in the BDL and CCl 4 control/sham groups was observed, which we attribute to the differences in age, sex and strain of rats used.…”

Role of the microRNA-29 family in fibrotic skin diseases

“…Skin fibrosis progression may be followed by chronic inflammation, inflammation and intrinsic profibrotic changes in fibroblasts, and involves cytokines, growth factors and different cell types (2,8). Endothelial cells, when damaged, release certain cytokines that activate immune cells.…”

“…Progression of fibrosis is a complex process and consists of immune, autoimmune and inflammatory mechanisms, as well as certain cytokines and chemical or physical factors (1,2). Fibrotic skin diseases may be accompanied by psychological issues, as a result of reduced self-esteem.…”

Cathepsin G Inhibitor Prevents Ultraviolet B- Induced Photoaging in Hairless Mice via Inhibition of Fibronectin Fragmentation

“…MMP expression is also increased indirectly by various cytokines, including interleukin (IL)-1α and IL-6 secreted from keratinocytes [5]. In addition, fragments of ECM that are produced from degraded fibronectin (Fn) in the chondrocytes of arthritic patients [6,7,8,9] or from damaged collagen in fibrotic skin upregulate MMP expression [10]. The resulting disruption of ECM integrity may impair the attachment of fibroblasts to the matrix, thereby decreasing the mechanical tension on the cells.…”