RRC ID 27899
Author Maeda K, Kobayashi Y, Udagawa N, Uehara S, Ishihara A, Mizoguchi T, Kikuchi Y, Takada I, Kato S, Kani S, Nishita M, Marumo K, Martin TJ, Minami Y, Takahashi N.
Title Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis.
Journal Nat Med
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.
Volume 18(3)
Pages 405-12
Published 2012-2-19
DOI 10.1038/nm.2653
PII nm.2653
PMID 22344299
MeSH Animals Arthritis / metabolism Bone Diseases / metabolism Cell Lineage Gene Expression Regulation MAP Kinase Kinase 4 / metabolism Mice Osteoblasts / cytology Osteoblasts / metabolism* Osteoclasts / cytology Osteoclasts / metabolism* Promoter Regions, Genetic Proto-Oncogene Proteins c-jun / genetics Proto-Oncogene Proteins c-jun / metabolism Receptor Activator of Nuclear Factor-kappa B / genetics Receptor Activator of Nuclear Factor-kappa B / metabolism Receptor Tyrosine Kinase-like Orphan Receptors / deficiency Receptor Tyrosine Kinase-like Orphan Receptors / genetics Receptor Tyrosine Kinase-like Orphan Receptors / metabolism* Skull / cytology Skull / growth & development Wnt Proteins / deficiency Wnt Proteins / genetics Wnt Proteins / metabolism* Wnt Signaling Pathway* Wnt-5a Protein X-Ray Microtomography
IF 30.641
Times Cited 244
Mice B6.Cg-Tg(CAG-floxed Neo-EGFP)REP08Osb(RBRC02096) B6-Tg(CAG-FLPe)36(RBRC01834)