Bile acids and bilirubin effects on osteoblastic gene profile. Implications in the pathogenesis of osteoporosis in liver diseases

Ruiz-Gaspà, Sílvia; Guañabens, Núria; Jurado, Susana Beatriz; Dubreuil, Marta; Combalía, Andrés; Peris, Pilar; Monegal, Ana; Parés, Albert

doi:10.1016/j.gene.2019.144167

Cited by 21 publications

(15 citation statements)

References 41 publications

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“…Cholesterol is the precursor of vitamin D, bile acids, and steroid hormones, all of which are important regulators of bone metabolism (Hoppel, 2003;Hernandez et al, 2019). BAs regulate the homeostasis of cholesterol, glucose and fat-soluble vitamins, and play a crucial role in maintaining mineral homeostasis (Ma and Patti, 2014;Ruiz-Gaspà et al, 2020). DCA and TCA differed notably in bone tissues of old mice and young mice models of FIGURE 4 | OPLS-DA plot of absolute quantitation of BAs (A).…”

Section: Discussionmentioning

confidence: 99%

An Integrated Metabolomic Study of Osteoporosis: Discovery and Quantification of Hyocholic Acids as Candidate Markers

Deng

Chen

Wu³

et al. 2021

Front. Pharmacol.

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Osteoporosis is becoming a highly prevalent disease in a large proportion of the global aged population. Serum metabolite markers may be important for the treatment and early prevention of osteoporosis. Serum samples from 32 osteoporosis and 32 controls were analyzed by untargeted metabolomics and lipidomic approaches performed on an ultra-high performance liquid chromatography and high-resolution mass spectrometry (UHPLC-HRMS) system. To find systemic disturbance of osteoporosis, weighted gene correlation network analysis (WGCNA) and statistical methods were employed for data-mining. Then, an in-depth targeted method was utilized to determine potential markers from the family of key metabolites. As a result, 1,241 metabolites were identified from untargeted methods and WGCNA indicated that lipids metabolism is deregulated and glycerol phospholipids, sphingolipids, fatty acids, and bile acids (BA) are majorly affected. As key metabolites of lipids metabolism, 66 bile acids were scanned and 49 compounds were quantified by a targeted method. Interestingly, hyocholic acids (HCA) were found to play essential roles during the occurrence of osteoporosis and may be potential markers. These metabolites may be new therapeutic or diagnosis targets for the screening or treatment of osteoporosis. Quantified measurement of potential markers also enables the establishment of diagnostic models for the following translational research in the clinic.

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Section: Discussionmentioning

confidence: 99%

An Integrated Metabolomic Study of Osteoporosis: Discovery and Quantification of Hyocholic Acids as Candidate Markers

Deng

Chen

Wu³

et al. 2021

Front. Pharmacol.

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“…The role of bile acids in bone turnover is complex and not well-defined. For instance, the bile acid lithocholic acid can upregulate the expression of RANKL in osteoblasts that may enhance the formation of osteoclasts within the basic multicellular unit [ 55 ], whereas global deletion of the bile acid receptor (FXR) in mice increased the number and size of osteoclasts [ 56 ]. Considering that bile acids are critically important for the emulsification and absorption of fatty acids and fat-soluble vitamins (e.g., vitamin D, vitamin E), the association between bile acid metabolism and CTX may be partly driven by the other lipid-related metabolic pathways associated with CTX.…”

Section: Discussionmentioning

confidence: 99%

Metabolomic Associations with Serum Bone Turnover Markers

et al. 2020

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Bone is a dynamic tissue that is in a constant state of remodeling. Bone turnover markers (BTMs), procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX), provide sensitive measures of bone formation and resorption, respectively. This study used ultra-high-resolution metabolomics (HRM) to determine plasma metabolic pathways and targeted metabolites related to the markers of bone resorption and formation in adults. This cross-sectional clinical study included 34 adults (19 females, mean 27.8 years), without reported illnesses, recruited from a US metropolitan area. Serum BTM levels were quantified by an ELISA. Plasma HRM utilized dual-column liquid chromatography and mass spectrometry to identify metabolites and metabolic pathways associated with BTMs. Metabolites significantly associated with P1NP (p < 0.05) were significantly enriched in pathways linked to the TCA cycle, pyruvate metabolism, and metabolism of B vitamins important for energy production (e.g., niacin, thiamin). Other nutrition-related metabolic pathways associated with P1NP were amino acid (proline, arginine, glutamate) and vitamin C metabolism, which are important for collagen formation. Metabolites associated with CTX levels (p < 0.05) were enriched within lipid and fatty acid beta-oxidation metabolic pathways, as well as fat-soluble micronutrient pathways including, vitamin D metabolism, vitamin E metabolism, and bile acid biosynthesis. P1NP and CTX were significantly related to microbiome-related metabolites (p < 0.05). Macronutrient-related pathways including lipid, carbohydrate, and amino acid metabolism, as well as several gut microbiome-derived metabolites were significantly related to BTMs. Future research should compare metabolism BTMs relationships reported here to aging and clinical populations to inform targeted therapeutic interventions.

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“…These results are consistent with those found in our recent publication, in which we analysed the impact of the same agents on gene expression in the osteoblastic cell line SAOS‐2 . 30 The effects of bilirubin, LCA and UDCA on gene expression were predominantly in human bone, which included mainly osteocytes but osteoblasts and osteoclasts as well. Thus, human bone tissue cultures retain the relative contribution of osteocytes, osteoblasts and osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

“…Total cellular RNA was extracted from MLO‐A5, MLO‐Y4 and bone fragments using an acid guanidinium‐phenol‐chloroform method (Trizol reagent; Invitrogen) according to the manufacturer's protocols, as formerly reported . 9‐11,30 Designed human or murine Taqman assays (Applied Biosystems) were used to quantify gene expression by Real‐Time PCR (performed in triplicate) of OPG , RANKL , RUNX2 , SP7 and BGLAP , selected as bone remodelling regulators. Results were expressed as relative expression (vs β‐actin gene expression), using arbitrary units according to the comparative Ct (threshold cycle) method .…”

Section: Methodsmentioning

confidence: 99%

Bilirubin and bile acids in osteocytes and bone tissue. Potential role in the cholestatic‐induced osteoporosis

Ruiz-Gaspà

Guañabens

Jurado

et al. 2020

Liver International

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Background and Aims: Osteoporosis is a common complication in patients with primary biliary cholangitis. Both bilirubin and lithocholic acid (LCA) result in detrimental effects on osteoblastic cells, and ursodeoxycholic acid (UDCA) counteracts these outcomes. However, there is no information on the consequences of these retained substances of cholestasis and sera from cholestatic patients in osteocytes. Methods: The impact of bilirubin, LCA, UDCA and serum from jaundiced patients on viability, differentiation, mineralization and apoptosis has been assessed in MLO-Y4 and MLO-A5 osteocyte cell lines. Effects on gene expression were assessed in these cells and in human bone fragments. Results: Lithocholic acid 10 μmol/L and bilirubin 50 μmol/L decreased viability in MLO-Y4 and MLO-A5 cells (11% and 53% respectively; P ≤ .01). UDCA alone or combined with LCA or bilirubin increased cell viability. Jaundiced sera decreased cell viability (56%), an effect which was reverted by UDCA. Bilirubin decreased differentiation by 47% in MLO-Y4 (P ≤ .01) and mineralization (87%) after 21 days in MLO-A5 (P ≤ .03). Both bilirubin and LCA increased apoptosis in MLO-Y4, and UDCA diminished the apoptotic effect. Moreover, bilirubin down-regulated RUNX2 and upregulated RANKL gene expression in bone tissue, MLO-Y4 and MLO-A5 cells, and LCA up-regulated RANKL expression in bone tissue. UDCA 100 μmol/L increased the gene expression of all these genes in bone tissue and MLO-Y4 cells and neutralized the decreased RUNX2 expression induced by bilirubin. Conclusion: Bilirubin and LCA have damaging consequences in osteocytes by decreasing viability, differentiation and mineralization, increasing apoptosis and modifying gene expression, effects that are neutralized by UDCA.

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Bile acids and bilirubin effects on osteoblastic gene profile. Implications in the pathogenesis of osteoporosis in liver diseases

Abstract: Bile acids and bilirubin effects on osteoblastic gene profile.Implications in the pathogenesis of osteoporosis in liver diseases.

Cited by 21 publications

References 41 publications

An Integrated Metabolomic Study of Osteoporosis: Discovery and Quantification of Hyocholic Acids as Candidate Markers

An Integrated Metabolomic Study of Osteoporosis: Discovery and Quantification of Hyocholic Acids as Candidate Markers

Metabolomic Associations with Serum Bone Turnover Markers

Bilirubin and bile acids in osteocytes and bone tissue. Potential role in the cholestatic‐induced osteoporosis

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