Influence of PSC on skeletal remodeling

骨质疏松性骨折是PSC患者发病和生活质量下降的主要原因，但其潜在的细胞和分子原因仍不清楚。我们在CRU 306项目8中进行的转化研究旨在研究PSC相关骨丢失的机制。在第一个资助期，我们发现PSC患者（n=238）的低骨量与钙稳态紊乱无关，但与骨吸收增加和Th 17细胞频率增加有关。此外，在PSC小鼠模型（Mdr 2缺陷小鼠）中缺失或抗体介导的IL-17阻断通过减少破骨细胞生成纠正了观察到的骨质减少。在显示骨质疏松症（n=15）或高骨量（n=12）的PSC患者的亚组分析中，我们通过脂质组学分析另外确定了循环胆汁酸浓度的显著差异。由于这种差异既不能用肝纤维化的差异来解释，也不能用并存的结肠炎或UDCA的差异治疗来解释，（熊去氧胆酸），高浓度的GUDCA（甘氨熊去氧胆酸）虽然我们在第一个资助期获得的研究结果表明，Th 17细胞的频率增加，与PSC中骨吸收相关，我们推测胆汁酸代谢的差异也可能导致PSC患者骨重建状态受损。在这种情况下，我们特别旨在比较PSC患者显示高或低骨量的帮助下，生物信息学的方法。如果这导致确定与骨量，微生物学，基因表达和/或胆汁成分相关的特定模式，这肯定会增加我们对PSC发病机制和并发症的生物学理解。在第二个供资期，我们希望进行以下研究。首先，我们将评估PSC患者骨病变的进展和抗吸收治疗对随访的影响。其次，我们将比较低或高骨量的PSC患者的各种骨骼和非骨骼参数。第三，我们将通过细胞培养实验或小鼠冷暴露来分析胆汁酸对骨重建的影响。由于我们的方法包括与CRU 306的其他合作伙伴的广泛合作，我们确实相信我们将产生新的和临床相关的信息来解释PSC相关的骨病理。

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.