Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence

Telomere shortening is a trigger of cellular senescence. Biliary epithelial cells in damaged small bile ducts in primary biliary cirrhosis (PBC) show senescent features such as the expression of senescence-associated β-galactosidase and the increased expression of p16INK4a and p21WAF1/Cip1. We investigated whether the telomere shortening is involved in the pathogenesis of biliary cellular senescence in PBC. We analyzed the telomere length of biliary epithelial cells using quantitative fluorescence in situ hybridization in livers taken from the patients with PBC (n = 13) and control livers (n = 13). We also assessed immunohistochemically the prevalence of DNA damage and the expression of p16INK4a and p21WAF1/Cip1. The study showed a significant decrease in telomere length in biliary epithelial cells in the damaged small bile ducts and bile ductules in PBC compared with normal-looking bile ducts and bile ductules in PBC, chronic viral hepatitis, and normal livers (P < 0.01). γH2AX-DNA-damage-foci were detected in biliary epithelial cells in damaged small bile ducts and bile ductules in PBC but were absent in biliary epithelial cells in chronic viral hepatitis and normal livers. The expression of p16INK4a and p21WAF1/Cip1 was increased corresponding to telomere shortening and γH2AX-DNA-damage-foci in the damaged small bile ducts in PBC. Conclusion: Telomere shortening and an accumulation of DNA damage coincide with increased expression of p16INK4a and p21WAF1/Cip1 in the damaged bile ducts, characterize biliary cellular senescence, and may play a role in the following progressive bile duct loss in PBC. (HEPATOLOGY 2008.)