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Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis

Nature Medicine volume 18, pages 405–412 (2012)Cite this article

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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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Figure 1: Impaired osteoclastogenesis in Wnt5a+/− and Ror2+/− mice.
Figure 2: Cause of impaired osteoclastogenesis in Ror2 and Wnt5a mutant mice.
Figure 3: Impaired osteoclastogenesis in Ror2 cKO and osteoblast-lineage cell-specific Wnt5a-deficient mice.
Figure 4: JNK, a noncanonical Wnt pathway is involved in Wnt5a-induced RANK expression in osteoclast precursors.
Figure 5: Wnt5a transactivates Tnfrsf11a by interaction of Jun with Sp1 sites in osteoclast precursors.
Figure 6: Wnt5a-Ror2 signaling is involved in bone destruction in collagen-induced arthritis (CIA) mice.

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Acknowledgements

We thank T. Kitamura (Tokyo University) for pMX-IRES-GFP vectors and Plat-E cells; M. Sakoda, S. Kinugawa, Y. Nakamichi and T. Yamashita for technical assistance; A. Yamaguchi, H. Takayanagi and T. Nakashima for thoughtful discussion; and T. Nishizawa, Y. Ueno and M. Saito for discussions about mice models. This work was supported by a Grant-in-Aid for Scientific Research (18390495, 22390351 (N.T.); 18390557, 21390551 (Y. Kobayashi); 19390476, 21390498 (N.U.)) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a grant from the Naito Foundation (Y. Kobayashi).

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  1. Kazuhiro Maeda and Yasuhiro Kobayashi: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute for Oral Science, Matsumoto Dental University, Nagano, Japan

    Kazuhiro Maeda, Yasuhiro Kobayashi, Toshihide Mizoguchi & Naoyuki Takahashi

  2. Department of Orthopedic Surgery, The Jikei University School of Medicine, Tokyo, Japan

    Kazuhiro Maeda & Keishi Marumo

  3. Department of Biochemistry, Matsumoto Dental University, Nagano, Japan

    Nobuyuki Udagawa & Shunsuke Uehara

  4. Department of Periodontology, Matsumoto Dental University, Nagano, Japan

    Akihiro Ishihara

  5. Department of Microbiology, Matsumoto Dental University, Nagano, Japan

    Yuichiro Kikuchi

  6. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    Ichiro Takada

  7. Laboratory of Nuclear Signaling, Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo, Japan

    Shigeaki Kato

  8. Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Developmental Biology, Hyogo, Japan

    Shuichi Kani

  9. Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Hyogo, Japan

    Shuichi Kani, Michiru Nishita & Yasuhiro Minami

  10. St. Vincent Institute of Medical Research, Victoria, Australia

    T John Martin

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Contributions

K.M. and Y. Kobayashi contributed equally to the manuscript, conducting most of the experiments and cooperating in the preparation of the manuscript. N.U., S.U., I.T., S. Kato, K.M. and T.J.M. supported the in vivo experiments, conducting the data analysis, and contributed to the manuscript preparation. T.M., A.I. and Y. Kikuchi carried out the immunohistochemistry and purified recombinant proteins. S. Kani, M.N. and Y.M. generated Ror2-deficient, Ror2-floxed mice and Ror2-specific antibodies and contributed to the data analysis. Y. Kobayashi generated Tnfrsf11aCre/+ and Wnt5a-floxed mice. Y. Kobayashi and N.T. designed and supervised the project and wrote the manuscript.

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Correspondence to Yasuhiro Kobayashi or Naoyuki Takahashi.

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Maeda, K., Kobayashi, Y., Udagawa, N. et al. Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis. Nat Med 18, 405–412 (2012). https://doi.org/10.1038/nm.2653

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