Abstract:Primary biliary cholangitis and primary sclerosing cholangitis (PSC) are the most common cholestatic liver diseases (CLD) in adults and are both characterized by an immune pathogenesis. While primary biliary cholangitis is a model autoimmune disease, with over 90% of patients presenting very specific autoantibodies against mitochondrial antigens, PSC is considered an immune mediated disease. Osteoporosis is the most common bone disease in CLD, resulting in frequent fractures and leading to significant morbidit… Show more
“…For example, pyogenic spondylodiscitis is able to cause severe osteolytic and destructive lesions 37 , while osteomyelitis and osteoporosis can both lead to loss of bone mass, where infections can alter RANKL-RANK-OPG signaling that is involved in the regulation of osteoblast and osteoclast behavior 38 . Furthermore, osteoporosis is an oft-occurring bone disease in cholestatic liver diseases, like primary biliary cholangitis and primary sclerosing cholangitis 39 . Fig.…”
Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).
“…For example, pyogenic spondylodiscitis is able to cause severe osteolytic and destructive lesions 37 , while osteomyelitis and osteoporosis can both lead to loss of bone mass, where infections can alter RANKL-RANK-OPG signaling that is involved in the regulation of osteoblast and osteoclast behavior 38 . Furthermore, osteoporosis is an oft-occurring bone disease in cholestatic liver diseases, like primary biliary cholangitis and primary sclerosing cholangitis 39 . Fig.…”
Due to a rapidly aging global population, osteoporosis and the associated risk of bone fractures have become a wide-spread public health problem. However, osteoporosis is very heterogeneous, and the existing standard diagnostic measure is not sufficient to accurately identify all patients at risk of osteoporotic fractures and to guide therapy. Here, we constructed the first prospective multi-omics atlas of the largest osteoporosis cohort to date (longitudinal data from 366 participants at three time points), and also implemented an explainable data-intensive analysis framework (DLSF: Deep Latent Space Fusion) for an omnigenic model based on a multi-modal approach that can capture the multi-modal molecular signatures (M3S) as explicit functional representations of hidden genotypes. Accordingly, through DLSF, we identified two subtypes of the osteoporosis population in Chinese individuals with corresponding molecular phenotypes, i.e., clinical intervention relevant subtypes (CISs), in which bone mineral density benefits response to calcium supplements in 2-year follow-up samples. Many snpGenes associated with these molecular phenotypes reveal diverse candidate biological mechanisms underlying osteoporosis, with xQTL preferences of osteoporosis and its subtypes indicating an omnigenic effect on different biological domains. Finally, these two subtypes were found to have different relevance to prior fracture and different fracture risk according to 4-year follow-up data. Thus, in clinical application, M3S could help us further develop improved diagnostic and treatment strategies for osteoporosis and identify a new composite index for fracture prediction, which were remarkably validated in an independent cohort (166 participants).
“…Cholestasis comprises primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which are the most typical forms of cholestasis in adults (Pugliese et al, 2022). At present, only ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are approved by the Food and Drug Administration for treating PBC.…”
Section: Introductionmentioning
confidence: 99%
“…If left untreated, it may lead to liver fibrosis, cirrhosis, and even liver carcinoma, such as cholangiocarcinoma or hepatocellular carcinoma (Pollock & Minuk, 2017). Cholestasis comprises primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which are the most typical forms of cholestasis in adults (Pugliese et al, 2022). At present, only ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) are approved by the Food and Drug Administration for treating PBC.…”
Cholestasis is a pathological condition characterized by disruptions in bile flow, leading to the accumulation of bile acids (BAs) in hepatocytes. Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by α‐naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC‐MS/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and β‐muricholic acid (β‐MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase Cyp8b1, while enhancing the expression of hepatic efflux transporter Mrp4, as well as the renal efflux transporters Mdr1 and Mrp2. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT‐induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.
“…5 Adults suffering from cholestatic liver diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) have also displayed similar correlations, although data on the latter are limited. 1,6 While the association between PBC and osteoporosis is well established, recent studies also suggest a higher prevalence of sarcopenia in patients with PBC compared to other liver diseases [7][8][9] Reports in PSC, which is also associated with osteoporosis, are scarce, and its correlation with sarcopenia is still being investigated. 6 Although dual-energy x-ray absorptiometry (DEXA) is not the preferred method for measuring sarcopenia, it allows the simultaneous assessment of muscle and bone mass without exposing patients to excessive radiation or incurring the significant costs associated with alternative approaches.…”
LINKED CONTENTThis article is linked to Thomson et al papers. To view these articles, visit https://doi.org/10.1111/apt.17823 and https://doi.org/10.1111/apt.17877
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