Influence of PSC on skeletal remodeling

骨质疏松性骨折是PSC患者发病率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CRU306项目8中进行的翻译研究旨在研究PSC相关骨丢失的机制。在第一个资助阶段，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Th17细胞频率增加有关。此外，在pSC(mdr2缺陷小鼠)的小鼠模型中，IL-17的缺失或抗体介导的阻断通过减少破骨细胞的生成来纠正所观察到的骨量减少。在对表现为骨质疏松症(n=15)或高骨量(n=12)的PSC患者的亚组分析中，我们还通过脂组分析发现循环胆汁酸浓度存在显着差异。由于这种差异既不是因为肝纤维化的差异，也不是因为并存的结肠炎或UDCA(熊去氧胆酸)的区别治疗，所以骨质疏松PSC患者血清中高浓度的GUDCA(甘草脱氧胆酸)只能通过这种外源性胆汁酸的不同代谢来解释。尽管我们在第一个资助期的研究结果表明，Th17细胞频率的增加与PSC的骨吸收有关，但我们假设胆汁酸代谢的差异也可能导致PSC患者受损的骨重建状态。在此背景下，我们特别致力于通过生物信息学方法比较显示骨量高或低的PSC患者。如果这项研究能够确定与骨量、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。在第二个资助期，我们希望进行以下研究。首先，我们将在PSC患者的随访中评估骨病理的进展和抗吸收治疗的影响。其次，我们将比较骨量低或高的PSC患者在各种骨骼和非骨骼参数方面的差异。第三，通过细胞培养实验和小鼠冷暴露实验，分析胆汁酸对骨重建的影响。由于我们的方法包括与CRU306的其他合作伙伴的广泛合作，我们相信我们将产生新的和临床相关的信息来解释PSC相关的骨骼病理。

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.