Tobias Schmidt1, Dorothee Schwinge2, Tim Rolvien1, Anke Jeschke3, Constantin Schmidt3, Mona Neven3, Sebastian Butscheidt3, Marvin Kriz2, Lilly Kunzmann2, Haider Mussawy4, Jan Hubert4, Thelonius Hawellek4, Wolfgang Rüther4, Ralf Oheim5, Florian Barvencik5, Ansgar W Lohse6, Christoph Schramm6, Thorsten Schinke3, Michael Amling7. 1. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 2. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 3. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 4. Department of Orthopedics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 5. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 6. First Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. 7. Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany; Martin Zeitz Center for Rare Diseases, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany. Electronic address: amling@uke.de.
Abstract
BACKGROUND & AIMS: Osteoporotic fractures are a major cause of morbidity and reduced quality of life in patients with primary sclerosing cholangitis (PSC), a progressive bile duct disease of unknown origin. Although it is generally assumed that this pathology is a consequence of impaired calcium homeostasis and malabsorption, the cellular and molecular causes of PSC-associated osteoporosis are unknown. METHODS: We determined bone mineral density by dual-X-ray absorptiometry and assessed bone microstructure by high-resolution peripheral quantitative computed tomography in patients with PSC. Laboratory markers of liver and bone metabolism were measured, and liver stiffness was assessed by FibroScan. We determined the frequency of Th17 cells by the ex vivo stimulation of peripheral blood mononuclear cells in a subgroup of 40 patients with PSC. To investigate the potential involvement of IL-17 in PSC-associated bone loss, we analyzed the skeletal phenotype of mice lacking Abcb4 and/or Il-17. RESULTS: Unlike in patients with primary biliary cholangitis, bone loss in patients with PSC was not associated with disease duration or liver fibrosis. However, we observed a significant negative correlation between the bone resorption biomarker deoxypyridinoline and bone mineral density in the PSC cohort, indicating increased bone resorption. Importantly, the frequency of Th17 cells in peripheral blood was positively correlated with the urinary deoxypyridinoline level and negatively correlated with bone mass. We observed that Abcb4-deficient mice displayed a low-bone-mass phenotype, which was corrected by an additional Il-17 deficiency or anti-IL-17 treatment, whereas the liver pathology was unaffected. CONCLUSIONS: Our findings demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC. Whether antibody-based IL-17 blockade is beneficial against bone loss in patients with PSC should be addressed in future studies. LAY SUMMARY: Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive bile duct destruction. One serious complication of PSC is reduced bone mass resulting in increased fracture risk. Herein, we demonstrate that Th17 cells mediate bone loss in PSC by inducing bone resorption, which suggests that antibody-based IL-17 blockade might be beneficial for the treatment of bone loss in affected patients.
BACKGROUND & AIMS:Osteoporotic fractures are a major cause of morbidity and reduced quality of life in patients with primary sclerosing cholangitis (PSC), a progressive bile duct disease of unknown origin. Although it is generally assumed that this pathology is a consequence of impaired calcium homeostasis and malabsorption, the cellular and molecular causes of PSC-associated osteoporosis are unknown. METHODS: We determined bone mineral density by dual-X-ray absorptiometry and assessed bone microstructure by high-resolution peripheral quantitative computed tomography in patients with PSC. Laboratory markers of liver and bone metabolism were measured, and liver stiffness was assessed by FibroScan. We determined the frequency of Th17 cells by the ex vivo stimulation of peripheral blood mononuclear cells in a subgroup of 40 patients with PSC. To investigate the potential involvement of IL-17 in PSC-associated bone loss, we analyzed the skeletal phenotype of mice lacking Abcb4 and/or Il-17. RESULTS: Unlike in patients with primary biliary cholangitis, bone loss in patients with PSC was not associated with disease duration or liver fibrosis. However, we observed a significant negative correlation between the bone resorption biomarker deoxypyridinoline and bone mineral density in the PSC cohort, indicating increased bone resorption. Importantly, the frequency of Th17 cells in peripheral blood was positively correlated with the urinary deoxypyridinoline level and negatively correlated with bone mass. We observed that Abcb4-deficient mice displayed a low-bone-mass phenotype, which was corrected by an additional Il-17deficiency or anti-IL-17 treatment, whereas the liver pathology was unaffected. CONCLUSIONS: Our findings demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC. Whether antibody-based IL-17 blockade is beneficial against bone loss in patients with PSC should be addressed in future studies. LAY SUMMARY:Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive bile duct destruction. One serious complication of PSC is reduced bone mass resulting in increased fracture risk. Herein, we demonstrate that Th17 cells mediate bone loss in PSC by inducing bone resorption, which suggests that antibody-based IL-17 blockade might be beneficial for the treatment of bone loss in affected patients.