Fibrosis resolution involves more than collagen; key role of MMP12 in fibrosis recovery.

[Background] Hepatic fibrosis can resolve, especially after eradication of HCV. The accurate monitoring of fibrosis resolution is limited to invasive approaches at this time. The peptidome contains not only synthesized peptides, but also fragments of degraded proteins. The “degradome” may be a key source of new biomarkers for fibrosis resolution.[Methods] Hepatic fibrosis was induced by injecting mice with CCl₄ for 4 wks. Some mice were treated with an MMP-12 inhibitor after cessation of CCl₄ intoxication. Liver injury and fibrosis were monitored. Hepatic expression and activity were also determined. The release of degraded ECM peptides in the plasma was analyzed for peptide identification and quantification.[Results] Hepatic fibrosis rapidly resolved. However, some collagen fibrils were still present 28d after cessation of CCl₄. Despite this persistent collagen presence, expression of fibrosis markers were normalized. Likewise expression of all hepatic MMPs, except MMP12, was normalized at the 28d. The persistence of MMP12 was reflected by the peptide fragments. Significantly the septa in the inhibitor group was far less defined and the inhibition dramatically delayed fibrosis resolution.[Conclusion] These results indicate MMP-12 and its substrates could play key roles in fibrosis resolution, that impact overall collagen resolution. Further analysis of the degradomic results could lead to new biomarkers to predict mechanism and outcome in hepatic fibrosis.