title: Modeling hepatic osteodystrophy in Abcb4 deficient mice.
abstract: Hepatic osteodystrophy (HOD) denotes the alterations in bone morphology and metabolism frequently observed in patients with chronic liver diseases, in particular in case of cholestatic conditions. The molecular mechanisms underlying HOD are only partially understood. In the present study, we characterized the bone phenotypes of the ATP-binding cassette transporter B4 knockout mouse (Abcb4(-/-)), a well-established mouse model of chronic cholestatic liver disease, with the aim of identifying and characterizing a mouse model for HOD. Furthermore, we investigated the influence of vitamin D on bone quality in this model. The bone morphology analyses revealed reduced bone mineral contents as well as changes in trabecular bone architecture and decreased cortical bone densities in Abcb4(-/-) mice with severe liver fibrosis. We observed dysregulation of genes involved in bone remodeling (osteoprotegerin, osteocalcin, osteopontin) and vitamin D metabolism (7-dehydrocholesterol reductase, Gc-globulin, Cyp2r1, Cyp27a1) as well as alterations in calcium and vitamin D homeostasis. In addition, serum RANKL and TGF-β levels were increased in Abcb4(-/-) mice. Vitamin D dietary intervention did not restore the bone phenotypes of Abcb4(-/-) animals. We conclude that the Abcb4(-/-) mouse provides an experimental framework and a preclinical model to gain further insights into the molecular pathobiology of HOD and to study the systemic effects of therapeutic interventions.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hochrath
authors.forename: Sabrina
authors.initials: S
authors.lastname: Ehnert
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Ackert-Bicknell
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lau
authors.forename: Andrea
authors.initials: A
authors.lastname: Schmid
authors.forename: Marcin
authors.initials: M
authors.lastname: Krawczyk
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Jordanne
authors.initials: J
authors.lastname: Dunn
authors.forename: Kanishka
authors.initials: K
authors.lastname: Hiththetiya
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Kateryna
authors.initials: K
authors.lastname: Micklich
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: Britt
authors.initials: B
authors.lastname: Wildemann
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
authors.forename: Andreas K
authors.initials: AK
authors.lastname: Nüssler
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000235:genetics; D015502:Absorptiometry, Photon; D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000473:pathology*; D012080:Chronic Kidney Disease-Mineral and Bone Disorder / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000097202:ATP-Binding Cassette Sub-Family B Member 4
references.citation: PLoS One. 2010 Nov 22;5(11):e14073
references.pmid: 21124921
references.citation: Crit Rev Oral Biol Med. 2000;11(3):279-303
references.pmid: 11021631
references.citation: Intern Emerg Med. 2013 Aug;8(5):377-88
references.pmid: 22241574
references.citation: Nat Methods. 2005 Jun;2(6):403-4
references.pmid: 15908916
references.citation: Methods Mol Biol. 2009;530:463-509
references.pmid: 19266331
references.citation: J Hepatol. 1995 Jun;22(6):696-9
references.pmid: 7560864
references.citation: Cell. 1993 Nov 5;75(3):451-62
references.pmid: 8106172
references.citation: Hepatology. 2010 Jan;51(1):267-76
references.pmid: 19827165
references.citation: Gut. 1990 Jan;31(1):82-7
references.pmid: 2318434
references.citation: BMC Cell Biol. 2006 Mar 20;7:15
references.pmid: 16549026
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Mol Biol Cell. 2003 Jan;14(1):173-89
references.pmid: 12529435
references.citation: Clin Rev Allergy Immunol. 2005 Apr;28(2):147-57
references.pmid: 15879620
references.citation: Proteomics. 2006 Dec;6(24):6538-48
references.pmid: 17109383
references.citation: Gut. 2002 Feb;50 Suppl 1:i1-9
references.pmid: 11788576
references.citation: Comput Methods Biomech Biomed Engin. 1997;1(1):15-23
references.pmid: 11264794
references.citation: Trop Gastroenterol. 2010 Apr-Jun;31(2):82-6
references.pmid: 20862980
references.citation: Biochim Biophys Acta. 2011 Jan;1814(1):186-99
references.pmid: 20619365
references.citation: J Bone Miner Res. 1990 Jan;5(1):49-58
references.pmid: 2309578
references.citation: Eur J Clin Invest. 2010 Jan;40(1):25-34
references.pmid: 20055894
references.citation: J Bone Miner Res. 2001 Jul;16(7):1318-28
references.pmid: 11450708
references.citation: Nat Rev Endocrinol. 2013 Jan;9(1):43-55
references.pmid: 23147574
references.citation: FASEB J. 2012 Dec;26(12):5081-91
references.pmid: 22982378
references.citation: Radiol Clin North Am. 2010 May;48(3):601-21
references.pmid: 20609895
references.citation: Cell. 2007 Aug 10;130(3):456-69
references.pmid: 17693256
references.citation: Anal Biochem. 1981 Mar 15;112(1):70-5
references.pmid: 7258630
references.citation: J Cell Physiol. 2013 Jun;228(6):1149-53
references.pmid: 23139068
references.citation: Gastroenterology. 2010 Jun;138(7):2348-56
references.pmid: 20178794
references.citation: Liver Int. 2013 Aug;33(7):1029-38
references.pmid: 23560764
references.citation: Wien Med Wochenschr. 2008;158(19-20):553-7
references.pmid: 18998071
references.citation: J Bone Miner Res. 1999 Jul;14(7):1167-74
references.pmid: 10404017
references.citation: Gastroenterology. 2004 Jul;127(1):261-74
references.pmid: 15236191
references.citation: Mol Cell Endocrinol. 2005 Nov 24;243(1-2):19-26
references.pmid: 16219413
references.citation: J Bone Miner Res. 2004 May;19(5):794-801
references.pmid: 15068503
references.citation: Calcif Tissue Int. 2013 Feb;92(2):77-98
references.pmid: 22782502
references.citation: Cell Transplant. 2011;20(9):1465-77
references.pmid: 21294943
references.citation: World J Hepatol. 2011 Dec 27;3(12):300-7
references.pmid: 22216370
references.citation: Am J Surg Pathol. 1995 Dec;19(12):1409-17
references.pmid: 7503362
references.citation: Hepatology. 2004 Jan;39(1):117-28
references.pmid: 14752830
references.citation: Gastroenterology. 2002 Dec;123(6):2041-51
references.pmid: 12454860
references.citation: Clin Chem. 2006 Jul;52(7):1247-53
references.pmid: 16709624
references.citation: J Hepatol. 1997 Jan;26(1):138-45
references.pmid: 9148004
references.citation: Gastroenterology. 2011 Jan;140(1):180-8
references.pmid: 20955707
references.citation: J Biomech. 1969 Oct;2(4):477-80
references.pmid: 16335147
references.citation: Hepatology. 2012 Nov;56(5):1883-91
references.pmid: 22576297
references.citation: Arch Biochem Biophys. 1996 Aug 1;332(1):142-52
references.pmid: 8806719
references.citation: Arch Biochem Biophys. 2010 Nov 1;503(1):84-94
references.pmid: 20537977