title: Secretion of a truncated osteopetrosis-associated transmembrane protein 1 (OSTM1) mutant inhibits osteoclastogenesis through down-regulation of the B lymphocyte-induced maturation protein 1 (BLIMP1)-nuclear factor of activated T cells c1 (NFATc1) axis.
abstract: Genetic mutations in osteoclastogenic genes are closely associated with osteopetrotic bone diseases. Genetic defects in OSTM1 (osteopetrosis-associated transmembrane protein 1) cause autosomal recessive osteopetrosis in humans. In particular, OSTM1 mutations that exclude the transmembrane domain might lead to the production of a secreted form of truncated OSTM1. However, the precise role of the secreted form of truncated OSTM1 remains unknown. In this study, we analyzed the functional role of truncated OSTM1 in osteoclastogenesis. Here, we showed that a secreted form of truncated OSTM1 binds to the cell surface of osteoclast (OC) precursors and inhibits the formation of multinucleated OCs through the reduction of cell fusion and survival. Truncated OSTM1 significantly inhibited the expression of OC marker genes through the down-regulation of the BLIMP1 (B lymphocyte-induced maturation protein 1)-NFATc1 (nuclear factor of activated T cells c1) axis. Finally, we demonstrated that truncated OSTM1 reduces lipopolysaccharide-induced bone destruction in vivo. Thus, these findings suggest that autosomal recessive osteopetrosis patients with an OSTM1 gene mutation lacking the transmembrane domain produce a secreted form of truncated OSTM1 that inhibits osteoclastogenesis.
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Bongjin
authors.initials: B
authors.lastname: Shin
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Jungeun
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Eui-Soon
authors.initials: ES
authors.lastname: Park
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Seunga
authors.initials: S
authors.lastname: Choi
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Yu
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Jung Me
authors.initials: JM
authors.lastname: Hwang
authors.affiliation: From the Department of Microbiology and Molecular Biology and.
authors.forename: Hyeongseok
authors.initials: H
authors.lastname: Yun
authors.affiliation: the Division of Life Science, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Korea, and.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Chung
authors.affiliation: the Division of Life Science, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Korea, and the Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea.
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Hong
authors.affiliation: the Division of Life Science, Korea Basic Science Institute, 169-148 Gwahak-ro, Yuseong-gu, Daejeon 305-806, Korea, and the Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea.
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Choi
authors.affiliation: the Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawaku 142-8555, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Takami
authors.affiliation: From the Department of Microbiology and Molecular Biology and the Graduate School of Analytical Science and Technology (GRAST), Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 305-764, Korea, jrrho@cnu.ac.kr.
authors.forename: Jaerang
authors.initials: J
authors.lastname: Rho
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D002470:Cell Survival; D002478:Cells, Cultured; D015536:Down-Regulation; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000276:immunology / Q000502:physiology*; D010024:Osteoporosis / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; C509143:OSTM1 protein, mouse; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1
keywords: BLIMP1; Bone; Cell Differentiation; NFATc1; OSTM1; Osteoblast; Osteoclast; Osteoclastogenesis; Osteopetrosis; Osteoporosis