title: Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis.
abstract: The signaling molecule Wnt regulates bone homeostasis through β-catenin-dependent canonical and β-catenin-independent noncanonical pathways. Impairment of canonical Wnt signaling causes bone loss in arthritis and osteoporosis; however, it is unclear how noncanonical Wnt signaling regulates bone resorption. Wnt5a activates noncanonical Wnt signaling through receptor tyrosine kinase-like orphan receptor (Ror) proteins. We showed that Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhanced osteoclastogenesis. Osteoblast-lineage cells expressed Wnt5a, whereas osteoclast precursors expressed Ror2. Mice deficient in either Wnt5a or Ror2, and those with either osteoclast precursor-specific Ror2 deficiency or osteoblast-lineage cell-specific Wnt5a deficiency showed impaired osteoclastogenesis. Wnt5a-Ror2 signals enhanced receptor activator of nuclear factor-κB (RANK) expression in osteoclast precursors by activating JNK and recruiting c-Jun on the promoter of the gene encoding RANK, thereby enhancing RANK ligand (RANKL)-induced osteoclastogenesis. A soluble form of Ror2 acted as a decoy receptor of Wnt5a and abrogated bone destruction in mouse arthritis models. Our results suggest that the Wnt5a-Ror2 pathway is crucial for osteoclastogenesis in physiological and pathological environments and represents a therapeutic target for bone diseases, including arthritis.
authors.affiliation: Institute for Oral Science, Matsumoto Dental University, Nagano, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Uehara
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ishihara
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mizoguchi
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takada
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kani
authors.forename: Michiru
authors.initials: M
authors.lastname: Nishita
authors.forename: Keishi
authors.initials: K
authors.lastname: Marumo
authors.forename: T John
authors.initials: TJ
authors.lastname: Martin
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Minami
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001168:Arthritis / Q000378:metabolism; D001847:Bone Diseases / Q000378:metabolism; D019070:Cell Lineage; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism; D057050:Receptor Tyrosine Kinase-like Orphan Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012886:Skull / Q000166:cytology / Q000254:growth & development; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D055114:X-Ray Microtomography
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; C477010:Ror2 protein, mouse; D048670:MAP Kinase Kinase 4