Osteoprotegerin Is more than a Possible Serum Marker in Liver Fibrosis: A Study into Its Function in Human and Murine Liver
Adhyatmika Adhyatmika,
Leonie Beljaars,
Kurnia S. S. Putri,
Habibie Habibie,
Carian E. Boorsma,
Catharina Reker-Smit,
Theerut Luangmonkong,
Burak Guney,
Axel Haak,
Keri A. Mangnus,
Eduard Post,
Klaas Poelstra,
Kim Ravnskjaer,
Peter Olinga,
Barbro N. Melgert
Affiliations
Adhyatmika Adhyatmika
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Leonie Beljaars
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Kurnia S. S. Putri
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Habibie Habibie
Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Carian E. Boorsma
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Catharina Reker-Smit
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Theerut Luangmonkong
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Burak Guney
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Axel Haak
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Keri A. Mangnus
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Eduard Post
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Klaas Poelstra
Department of Pharmacokinetics, Toxicology, and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Kim Ravnskjaer
Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 M Odense M, Denmark
Peter Olinga
Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Barbro N. Melgert
Department of Molecular Pharmacology, Groningen Research Institute for Pharmacy, University of Groningen, 9713 AV Groningen, The Netherlands
Osteoprotegerin (OPG) serum levels are associated with liver fibrogenesis and have been proposed as a biomarker for diagnosis. However, the source and role of OPG in liver fibrosis are unknown, as is the question of whether OPG expression responds to treatment. Therefore, we aimed to elucidate the fibrotic regulation of OPG production and its possible function in human and mouse livers. OPG levels were significantly higher in lysates of human and mouse fibrotic livers compared to healthy livers. Hepatic OPG expression localized in cirrhotic collagenous bands in and around myofibroblasts. Single cell sequencing of murine liver cells showed hepatic stellate cells (HSC) to be the main producers of OPG in healthy livers. Using mouse precision-cut liver slices, we found OPG production induced by transforming growth factor β1 (TGFβ1) stimulation. Moreover, OPG itself stimulated expression of genes associated with fibrogenesis in liver slices through TGFβ1, suggesting profibrotic activity of OPG. Resolution of fibrosis in mice was associated with decreased production of OPG compared to ongoing fibrosis. OPG may stimulate fibrogenesis through TGFβ1 and is associated with the degree of fibrogenesis. It should therefore be investigated further as a possible drug target for liver fibrosis or biomarker for treatment success of novel antifibrotics.
