Urinary matrix metalloproteinases and their endogenous inhibitors predict hepatic regeneration after murine partial hepatectomy

Background. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix remodeling events associated with hepatic regeneration after partial hepatectomy. We therefore hypothesized that urinary MMPs and their endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) might also provide important information regarding initiation and progression of liver regeneration. Methods. Groups of 20 mice underwent sham operations, two-thirds hepatectomy, or treatment with the angiogenesis inhibitor, AGM-1470, O-chloroacetyl-carbamoyl-fumagillol (TNP-470), after two-thirds hepatectomy to prevent hepatic regeneration. Urine was collected preoperatively and for 24 days after surgery and tested for MMP-2, MMP-9, TIMP-1, and TIMP-2 using substrate gel electrophoresis (zymography) and Western blot analysis. Results. During hepatic regeneration, MMP-9 was detected in the urine at significantly lower levels on postoperative day 8 when the liver returned to its preoperative mass. In contrast, urine from mice whose livers were inhibited from regenerating (TNP-treated groups) contained increased levels of the gelatinases MMP-2 and MMP-9. The MMP inhibitors, TIMP-1 and TIMP-2, were significantly reduced in the urine of mice with normally regenerating livers but were increased in the urine of mice treated with TNP-470 on day 8. Conclusions. We demonstrate that (1) urinary MMPs and their cognate inhibitors, the TIMPs, can be detected in the urine of mice undergoing partial hepatectomy, (2) the presence of these remodeling proteins in the urine may predict the progressive return of the partially resected liver to its preoperative mass, and (3) analysis of urinary MMPs and TIMPs may someday provide a noninvasive means of monitoring the status of patients undergoing hepatic resection and transplantation.