Sclerostin Expression in Bile Ducts of Patients With Chronic Cholestasis May Influence the Bone Disease in Primary Biliary Cirrhosis.

Sclerostin is involved in the regulation of osteoblastogenesis and little is known about its role in the development of bone disease in primary biliary cirrhosis (PBC), characterized by low bone formation. Therefore, we have assessed the circulating levels and the liver expression of sclerostin in this cholestatic disease. Serum sclerostin levels were measured in 79 women with PBC (mean age 60.6 ± 1.2 years) and in 80 control women. Lumbar and femoral bone mineral density (BMD), as well as parameters of mineral metabolism and bone remodeling, were measured. Moreover, sclerostin gene (SOST) expression in the liver was assessed by real-time PCR in samples of liver tissue taken by biopsy in 11 PBC patients and in 5 normal liver specimens. Presence and distribution of sclerostin was evaluated in liver slices from 11 patients by immunohistochemistry. The severity of histologic lesions was assessed semiquantitatively in the same liver samples. PBC patients had higher sclerostin levels than controls (75.6 ± 3.9 versus 31.7 ± 1.6 pmol/L, p < 0.001). Serum sclerostin correlated inversely with markers of bone formation and resorption. Sclerostin mRNA in the liver was overexpressed compared with control samples (2.7-fold versus healthy liver). Sclerostin was detected by immunohistochemistry in 7 of the 11 liver samples, mainly located in the bile ducts. Liver sclerostin was associated with the severity of cholangitis (p = 0.02) and indirectly with the degree of lobular inflammation (p = 0.03). Sclerostin mRNA expression was higher in samples that tested positive by immunohistochemistry and particularly in those with lobular granuloma (p = 0.02). The increased expression of sclerostin in the liver and the association with histologic cholangitis may explain the high serum levels of this protein in patients with PBC, thus suggesting that sclerostin may influence the decreased bone formation in this cholestatic disease.