title: The paired-box homeodomain transcription factor Pax6 binds to the upstream region of the TRAP gene promoter and suppresses receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation.
abstract: Osteoclast formation is regulated by balancing between the receptor activator of nuclear factor-κB ligand (RANKL) expressed in osteoblasts and extracellular negative regulatory cytokines such as interferon-γ (IFN-γ) and interferon-β (IFN-β), which can suppress excessive bone destruction. However, relatively little is known about intrinsic negative regulatory factors in RANKL-mediated osteoclast differentiation. Here, we show the paired-box homeodomain transcription factor Pax6 acts as a negative regulator of RANKL-mediated osteoclast differentiation. Electrophoretic mobility shift and reporter assays found that Pax6 binds endogenously to the proximal region of the tartrate acid phosphatase (TRAP) gene promoter and suppresses nuclear factor of activated T cells c1 (NFATc1)-induced TRAP gene expression. Introduction of Pax6 retrovirally into bone marrow macrophages attenuates RANKL-induced osteoclast formation. Moreover, we found that the Groucho family member co-repressor Grg6 contributes to Pax6-mediated suppression of the TRAP gene expression induced by NFATc1. These results suggest that Pax6 interferes with RANKL-mediated osteoclast differentiation together with Grg6. Our results demonstrate that the Pax6 pathway constitutes a new aspect of the negative regulatory circuit of RANKL-RANK signaling in osteoclastogenesis and that the augmentation of Pax6 might therefore represent a novel target to block pathological bone resorption.
authors.affiliation: From the Departments ofMolecular Biology.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kogawa
authors.forename: Koji
authors.initials: K
authors.lastname: Hisatake
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Enoki
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Sato
authors.forename: Peter C
authors.initials: PC
authors.lastname: Gray
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kanesaki-Yatsuka
authors.forename: Paul H
authors.initials: PH
authors.lastname: Anderson
authors.forename: Seiki
authors.initials: S
authors.lastname: Wada
authors.forename: Naoki
authors.initials: N
authors.lastname: Kato
authors.forename: Aya
authors.initials: A
authors.lastname: Fukuda
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Katayama
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yoda
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Suda
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okazaki
authors.forename: Masahito
authors.initials: M
authors.lastname: Matsumoto
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D056970:Co-Repressor Proteins; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D056970:Co-Repressor Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D007527:Isoenzymes; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; C000605732:Pax6 protein, mouse; D053245:RANK Ligand; D012097:Repressor Proteins; C505688:TNFSF11 protein, human; C434948:Tle6 protein, mouse; C505689:Tnfsf11 protein, mouse; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Differentiation; Gene Regulation; Macrophages; Osteoclast; Pax6; TRAP; Transcription Factors