title: The Nuclear Receptor AhR Controls Bone Homeostasis by Regulating Osteoclast Differentiation via the RANK/c-Fos Signaling Axis.
abstract: The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-κB ligand (RANKL)-mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow-derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR-/-mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-κB, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos-dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a]pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR-/-mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan; and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Izawa
authors.affiliation: Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Arakaki
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan; and.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mori
authors.affiliation: Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tsunematsu
authors.affiliation: Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan.
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan; and.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
authors.affiliation: Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 7708504, Japan ishimaru.n@tokushima-u.ac.jp.
authors.forename: Naozumi
authors.identifier: 0000-0003-1087-8338
authors.initials: N
authors.lastname: Ishimaru
mesh_terms: D000818:Animals; D001580:Benzopyrenes / Q000378:metabolism; D001854:Bone Marrow Cells / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001580:Benzopyrenes; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D018336:Receptors, Aryl Hydrocarbon; C505689:Tnfsf11 protein, mouse