title: Overexpression of gamma-glutamyltransferase in transgenic mice accelerates bone resorption and causes osteoporosis.
abstract: We previously identified gamma-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-kappaB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-kappaB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.
authors.affiliation: Department of Bone and Joint Disease, Research Institute, National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hiramatsu
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Asaba
authors.forename: Sunao
authors.initials: S
authors.lastname: Takeshita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nimura
authors.forename: Sawako
authors.initials: S
authors.lastname: Tatsumi
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Katagiri
authors.forename: Shumpei
authors.initials: S
authors.lastname: Niida
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Sakae
authors.initials: S
authors.lastname: Tanaka
authors.forename: Masako
authors.initials: M
authors.lastname: Ito
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology; D010024:Osteoporosis / Q000235:genetics*; D053245:RANK Ligand / Q000235:genetics; D014078:Tooth Eruption / Q000235:genetics; D014162:Transfection; D005723:gamma-Glutamyltransferase / Q000235:genetics*
chemical_list: D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D005723:gamma-Glutamyltransferase