Procollagen type I N-terminal propeptide (PINP) is a marker for fibrogenesis in bile duct ligation-induced fibrosis in rats

BACKGROUND: Fibrosis can be described as the excess deposition of extracellular matrix (ECM) components, such as collagens and proteoglycans. Fibrosis of the liver, which eventually leads to cirrhosis, is a major global health problem. Being able to measure fibrosis progression may enable timely preventative intervention. The aim of the current study was to investigate the utility of serum procollagen type I N-terminal propeptide (PINP) as a marker of hepatic fibrosis, as distinct from bone formation, during three different periods of fibrosis development following hepatic injury induced by bile duct ligation (BDL) in rats. METHODS: BDL was performed on 30 female Sprague-Dawley rats aged 6 months, and sham operations on 30 controls. Animals were killed after 14, 28, or 35 days. The extent of liver fibrosis was evaluated by quantitative histology after Sirus Red staining. Levels of serum PINP and osteocalcin (a marker solely for osteoblastic bone formation) were determined using ELISA at baseline and post termination. RESULTS: Collagen formation increased by 30% compared to 3% in sham-operated animals (P < 0.0001). PINP levels increased significantly in all BDL groups compared with baseline (14 days: baseline 13.9 ng/ml, termination 17.7 ng/ml, P = 0.047; 28 days: baseline 17.9 ng/ml, termination 26.2 ng/ml, P = 0.005; 35 days: baseline 18.0 ng/ml, termination 27.4 ng/ml P = 0.015, an increase of 52%). PINP levels did not change from baseline in the sham-operated rats, indicating that the increased PINP levels were due to hepatic injury. The bone-specific marker, osteocalcin, did not increase in either BDL or sham-operated rats. PINP measured in serum correlated to the extent of liver fibrosis as evaluated by quantitative histology (R(2 )= 0.42, P < 0.001). CONCLUSION: PINP was associated with the development of liver fibrosis, but not bone formation, in mature rats subjected to BDL. Thus, PINP may be useful in studying the pathogenesis of liver fibrosis. However, caution should be applied when interpreting PINP levels in other disease states.