Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis
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Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis. / Schmidt, Tobias; Schwinge, Dorothee; Rolvien, Tim; Jeschke, Anke; Schmidt, Constantin; Neven, Mona; Butscheidt, Sebastian; Kriz, Marvin; Kunzmann, Lilly; Mussawy, Haider; Hubert, Jan; Hawellek, Thelonius; Rüther, Wolfgang; Oheim, Ralf; Barvencik, Florian; Lohse, Ansgar W; Schramm, Christoph; Schinke, Thorsten; Amling, Michael.
In: J HEPATOL, Vol. 70, No. 5, 05.2019, p. 941-953.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Th17 cell frequency is associated with low bone mass in primary sclerosing cholangitis
AU - Schmidt, Tobias
AU - Schwinge, Dorothee
AU - Rolvien, Tim
AU - Jeschke, Anke
AU - Schmidt, Constantin
AU - Neven, Mona
AU - Butscheidt, Sebastian
AU - Kriz, Marvin
AU - Kunzmann, Lilly
AU - Mussawy, Haider
AU - Hubert, Jan
AU - Hawellek, Thelonius
AU - Rüther, Wolfgang
AU - Oheim, Ralf
AU - Barvencik, Florian
AU - Lohse, Ansgar W
AU - Schramm, Christoph
AU - Schinke, Thorsten
AU - Amling, Michael
N1 - Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2019/5
Y1 - 2019/5
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1016/j.jhep.2018.12.035
DO - 10.1016/j.jhep.2018.12.035
M3 - SCORING: Journal article
C2 - 30641095
VL - 70
SP - 941
EP - 953
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 5
ER -