title: Osteodystrophy in Cholestatic Liver Diseases Is Attenuated by Anti-γ-Glutamyl Transpeptidase Antibody.
abstract: BACKGROUND
  Cholestatic liver diseases exhibit higher levels of serum γ-glutamyl transpeptidase (GGT) and incidence of secondary osteoporosis. GGT has been identified as a novel bone-resorbing factor that stimulates osteoclast formation. The aim of this study was to elucidate the interaction of elevated GGT levels and cholestatic liver disease-induced bone loss.
  
  
  METHODS
  Wistar rats were divided into three groups: sham-operated control (SO) rats, bile duct ligation (BDL) rats, and anti-GGT antibody-treated BDL rats (AGT). Serum GGT level was measured. Bone mineral density (BMD) was analyzed by dual-energy X-ray absorptiometry. Bone morphometric parameters and microarchitectural properties were determined by micro-computed tomography and histomorphometry of the distal metaphysis of femurs. Alterations of bone metabolism-related factors were evaluated by cytokine array. Effects of GGT on osteoblasts or stromal cells were evaluated by RT-PCR, enzyme activity, and mineralization ability.
  
  
  RESULTS
  Serum levels of GGT were significantly elevated in the BDL-group. In the BDL group, BMD, bone mass percentage, and osteoblast number were significantly decreased, whereas osteoclast number was significantly increased. These alterations were markedly attenuated in the AGT group. The mRNA levels of vascular endothelial growth factor-A, LPS-induced CXC chemokine, monocyte chemoattractant protein-1, tumor necrosis factor-α interleukin-1β and receptor activator of nuclear factor-kappa B ligand were upregulated, and those of interferon-γ and osteoprotegerin were downregulated in the GGT-treated stromal cells. Furthermore, GGT inhibited mineral nodule formation and expression of alkaline phosphatase and bone sialo-protein in osteoblastic cells.
  
  
  CONCLUSIONS
  Our results indicate that elevated GGT level is involved in hepatic osteodystrophy through secretion of bone resorbing factor from GGT-stimulated osteoblasts/bone marrow stromal cells. In addition, GGT also possesses suppressive effects on bone formation. Managing elevated GGT levels by anti-GGT antibody may become a novel therapeutic agent for hepatic osteodystrophy in chronic liver diseases.
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kawazoe
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Miyauchi
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Nagasaki
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Furusho
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Syunryo
authors.initials: S
authors.lastname: Yanagisawa
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Chea
authors.initials: C
authors.lastname: Chanbora
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Inubushi
authors.affiliation: Department of Medicine and Molecular Science, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Hyogo
authors.affiliation: Department of Oral and Maxillofacial Radiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakamoto
authors.affiliation: Department of Pharmacology, School of Dentistry, Showa University, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Biobank Omics Unit, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Moriwaki
authors.affiliation: Departments of General Internal Medicine, Hiroshima University Hospital, Hiroshima, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Tazuma
authors.affiliation: Biobank Omics Unit, National Center for Geriatrics and Gerontology, Aichi, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Niida
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
mesh_terms: D015502:Absorptiometry, Photon; D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008026:Ligation; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins; D005723:gamma-Glutamyltransferase