Effects of bilirubin and sera from jaundiced patients on osteoblasts: Contribution to the development of osteoporosis in liver diseases

Authors

  • Silvia Ruiz-Gaspà,

    Corresponding author
    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
    • CIBERehd, Metabolic Bone Diseases Unit, Hospital Clinic–IDIBAPS, Villarroel 170, 08036 Barcelona, Spain
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    • fax: +34-93-2271779

    • These authors contributed equally to this work.

  • Angels Martinez-Ferrer,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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    • These authors contributed equally to this work.

  • Nuria Guañabens,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Marta Dubreuil,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Pilar Peris,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Anna Enjuanes,

    1. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Maria Jesús Martinez de Osaba,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Luisa Alvarez,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Ana Monegal,

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Andrés Combalia,

    1. Metabolic Bone Diseases Unit, Department of RheumatologyUniversity of Barcelona, Barcelona, Spain
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  • Albert Parés

    1. Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd)University of Barcelona, Barcelona, Spain
    2. Liver Unit, Digestive Diseases Institute, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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  • Potential conflict of interest: Nothing to report.

Abstract

Low bone formation is considered to be the main feature in osteoporosis associated with cholestatic and end-stage liver diseases, although the consequences of retained substances in chronic cholestasis on bone cells have scarcely been studied. Therefore, we analyzed the effects of bilirubin and serum from jaundiced patients on viability, differentiation, mineralization, and gene expression in the cells involved in bone formation. The experiments were performed in human primary osteoblasts and SAOS-2 human osteosarcoma cells. Unconjugated bilirubin or serum from jaundiced patients resulted in a dose-dependent decrease in osteoblast viability. Concentrations of bilirubin or jaundiced serum without effects on cell survival significantly diminished osteoblast differentiation. Mineralization was significantly reduced by exposure to 50 μM bilirubin at all time points (from −32% to −55%) and jaundiced sera resulted in a significant decrease on cell mineralization as well. Furthermore, bilirubin down-regulated RUNX2 (runt-related transcription factor 2) gene expression, a basic osteogenic factor involved in osteoblast differentiation, and serum from jaundiced patients significantly up-regulated the RANKL/OPG (receptor activator of nuclear factor-κB ligand/osteoprotegerin) gene expression ratio, a system closely involved in osteoblast-induced osteoclastogenesis. Conclusion: Besides decreased cell viability, unconjugated bilirubin and serum from jaundiced patients led to defective consequences on osteoblasts. Moreover, jaundiced serum up-regulates the system involved in osteoblast-induced osteoclastogenesis. These results support the deleterious consequences of increased bilirubin in advanced chronic cholestasis and in end-stage liver diseases, resulting in disturbed bone formation related to osteoblast dysfunction. (HEPATOLOGY 2011)

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