MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay. / Veidal, Sanne Skovgård; Karsdal, Morten Asser; Vassiliadis, Efstathios; Nawrocki, Arkadiusz; Larsen, Martin Røssel; Nguyen, Quoc Hai Trieu; Hägglund, Per; Luo, Yunyun; Zheng, Qinlong; Vainer, Ben; Leeming, Diana Julie.
In: P L o S One, Vol. 6, No. 9, 2011, p. e24753.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay
AU - Veidal, Sanne Skovgård
AU - Karsdal, Morten Asser
AU - Vassiliadis, Efstathios
AU - Nawrocki, Arkadiusz
AU - Larsen, Martin Røssel
AU - Nguyen, Quoc Hai Trieu
AU - Hägglund, Per
AU - Luo, Yunyun
AU - Zheng, Qinlong
AU - Vainer, Ben
AU - Leeming, Diana Julie
PY - 2011
Y1 - 2011
N2 - BACKGROUND AND AIMS: During fibrogenesis, in which excessive remodeling of the extracellular matrix occurs, both the quantity of type VI collagen and levels of matrix metalloproteinases, including MMP-2 and MMP-9, increase significantly. Proteolytic degradation of type VI collagen into small fragments, so-called neo-epitopes, may be specific biochemical marker of liver fibrosis. The aim of this study was to develop an ELISA detecting a fragment of type VI collagen generated by MMP-2 and MMP-9, and evaluate this assay in two preclinical models of liver fibrosis.METHODS: Mass spectrometric analysis of cleaved type VI collagen revealed a large number of protease-generated neo-epitopes. A fragment unique to type VI collagen generated by MMP-2 and MMP-9 was selected for ELISA development. The CO6-MMP assay was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetrachloride (CCl4)-treated rats.RESULTS: Intra- and inter-assay variation was 4.1% and 10.1% respectively. CO6-MMP levels were significantly elevated in CCl(4)-treated rats compared to vehicle-treated rats at weeks 12 (mean 30.9 ng/mL vs. 12.8 ng/mL, p¿=¿0.002); week 16 (mean 34.0 ng/mL vs. 13.7 ng/mL, p¿=¿0.0018); and week 20 (mean 35.3 ng/mL vs. 13.3 ng/mL, p¿=¿0.0033) with a tight correlation between hepatic collagen content and serum levels of CO6-MMP (R(2)¿=¿0.58, p<0.0001) in CCl(4)- treated rats. In BDL rats, serum levels of CO6-MMP were significantly elevated compared to the levels in sham-operated animals both at 2 weeks (mean 29.5 ng/mL vs. 14.2 ng/mL, p¿=¿0.0001) and 4 weeks (mean 33.0 ng/mLvs. 11.8 ng/mL, p¿=¿0.0003).CONCLUSIONS: This novel ELISA is the first assay enabling assessment of MMP degraded type VI collagen, allowing quantification of type VI collagen degradation, which would be relevant for different pathologies. The marker was highly associated with liver fibrosis in two liver fibrosis animal models, suggesting type VI turnover to be a central player in fibrogenesis.
AB - BACKGROUND AND AIMS: During fibrogenesis, in which excessive remodeling of the extracellular matrix occurs, both the quantity of type VI collagen and levels of matrix metalloproteinases, including MMP-2 and MMP-9, increase significantly. Proteolytic degradation of type VI collagen into small fragments, so-called neo-epitopes, may be specific biochemical marker of liver fibrosis. The aim of this study was to develop an ELISA detecting a fragment of type VI collagen generated by MMP-2 and MMP-9, and evaluate this assay in two preclinical models of liver fibrosis.METHODS: Mass spectrometric analysis of cleaved type VI collagen revealed a large number of protease-generated neo-epitopes. A fragment unique to type VI collagen generated by MMP-2 and MMP-9 was selected for ELISA development. The CO6-MMP assay was evaluated in two rat models of liver fibrosis: bile duct ligation (BDL) and carbon tetrachloride (CCl4)-treated rats.RESULTS: Intra- and inter-assay variation was 4.1% and 10.1% respectively. CO6-MMP levels were significantly elevated in CCl(4)-treated rats compared to vehicle-treated rats at weeks 12 (mean 30.9 ng/mL vs. 12.8 ng/mL, p¿=¿0.002); week 16 (mean 34.0 ng/mL vs. 13.7 ng/mL, p¿=¿0.0018); and week 20 (mean 35.3 ng/mL vs. 13.3 ng/mL, p¿=¿0.0033) with a tight correlation between hepatic collagen content and serum levels of CO6-MMP (R(2)¿=¿0.58, p<0.0001) in CCl(4)- treated rats. In BDL rats, serum levels of CO6-MMP were significantly elevated compared to the levels in sham-operated animals both at 2 weeks (mean 29.5 ng/mL vs. 14.2 ng/mL, p¿=¿0.0001) and 4 weeks (mean 33.0 ng/mLvs. 11.8 ng/mL, p¿=¿0.0003).CONCLUSIONS: This novel ELISA is the first assay enabling assessment of MMP degraded type VI collagen, allowing quantification of type VI collagen degradation, which would be relevant for different pathologies. The marker was highly associated with liver fibrosis in two liver fibrosis animal models, suggesting type VI turnover to be a central player in fibrogenesis.
U2 - 10.1371/journal.pone.0024753
DO - 10.1371/journal.pone.0024753
M3 - Journal article
C2 - 21935455
VL - 6
SP - e24753
JO - PLoS ONE
JF - PLoS ONE
SN - 1932-6203
IS - 9
ER -
ID: 40222106