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.
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WNT5a produced by osteoblasts supports osteoclastogenesis by stimulating RANK expression in osteoclast precursors, promoting osteoclast fusion, and supporting actin ring formation and bone resorption via c-Src.
“WNT5a produced by osteoblasts supports osteoclastogenesis by stimulating RANK expression in osteoclast precursors,180 promoting osteoclast fusion,181 and supporting actin ring formation and bone resorption via c-Src.182”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [180]
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- Authors
- 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, T. J., Minami, Y., & Takahashi, N.
- Affiliations
- Matsumoto Dental University (JP)
- Keio University (JP)
- Institute for Quantitative Biosciences, The University of Tokyo (JP)
- RIKEN (JP)
- Kobe University (JP)
- Jikei University School of Medicine (JP)
- St Vincents Institute of Medical Research (AU)
- Corresponding author
- Kobayashi, Yasuhiro
- Takahashi, Naoyuki
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-02-19
- Volume
- 18
- Issue
- 3
- Pages
- 405-412
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2024499742
- Cited by
- 542
- References
- 60
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- FWCI
- 18.37
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- journal article
- Language
- en
- Open access
- closed
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- www.springer.com/tdm (tdm)
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- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (24390417, 23791668, 21390080, 22790291, 23650595, 22390351, 21390505, 23792134, 23659972, 24659833, 22659339, 23593054, 21390551, 23791662)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Keywords
- Wnt5a, ROR2, non-canonical Wnt signaling, osteoclastogenesis, osteoblast lineage cells, osteoclast precursors, RANK expression, RANKL, JNK, c-Jun, rheumatoid arthritis, bone homeostasis, bone resorption, decoy receptor, osteoporosis
- MeSH terms
- Wnt-5a Protein, Animals, Arthritis, Bone Diseases, Gene Expression Regulation, Osteoblasts, Osteoclasts, Promoter Regions, Genetic, Skull, Proto-Oncogene Proteins c-jun, Cell Lineage, MAP Kinase Kinase 4, Wnt Proteins, Mice, Receptor Activator of Nuclear Factor-kappa B, X-Ray Microtomography, Receptor Tyrosine Kinase-like Orphan Receptors, Wnt Signaling Pathway
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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