Project Details
Projekt
Influence of PSC on skeletal remodeling
Subject Area
Orthopaedics, Traumatology, Reconstructive Surgery
Term
from 2016 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 278045702
Osteoporotic fractures are a major cause of morbidity and reduced life quality in PSC patients, yet the underlying cellular and molecular causes are still unknown. Our translational study performed in project 8 of the CRU306 aims at investigating the mechanism for PSC-associated bone loss. In the first funding period we found that low bone mass in PSC patients (n=238) is not associated with disturbed calcium homeostasis, but with increased bone resorption and increased frequencies of Th17 cells. Moreover, deletion or antibody-mediated blockade of IL-17 in a mouse model of PSC (Mdr2-deficient mice) corrected the observed osteopenia by reducing osteoclastogenesis. In a subgroup analysis of PSC patients displaying either osteoporosis (n=15) or high bone mass (n=12) we additionally identified striking differences in the concentrations of circulating bile acids by lipidomic analysis. Since this divergence was neither explained by differences in liver fibrosis, nor by co-existing colitis or differential treatment with UDCA (ursodesoxycholic acid), the high concentration of GUDCA (glycoursodeoxycholic acid) in the serum of osteoporotic PSC patients can only be explained by differential metabolism of this exogenous bile acid.Although our findings obtained in the first funding period demonstrate that an increased frequency of Th17 cells is associated with bone resorption in PSC, we hypothesize that differences in bile acid metabolism may also contribute to the impaired bone remodeling status in PSC patients. In this context we particularly aim at comparing PSC patients displaying high or low bone mass with the help of bioinformatic approaches. Should this lead to the identification of specific patterns correlating bone mass, microbiology, gene expression and/or bile composition, this would certainly increase our biological understanding of PSC pathogenesis and complications. In the second funding period we want to perform the following studies. First, we will assess the progression of bone pathologies and the influence of anti-resorptive treatment in follow-up visits of PSC patients. Second, we will compare PSC patients with low or high bone mass with respect to various skeletal and non-skeletal parameters. Third, we will analyze the influence of bile acids on bone remodeling by cell culture experiments or cold exposure of mice. Since our approach includes extensive collaboration with the other partners of the CRU306, we truly believe that we will generate novel and clinically relevant information to explain PSC-associated bone pathologies.
DFG Programme
Clinical Research Units
Subproject of
KFO 306:
Primär Sklerosierende Cholangitis
