Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4−/−) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

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This work is supported by grants from the National Basic Research Program of China (2012CB910402 to J.L.; 2012CB910400 to M.L.), the National Natural Science Foundation of China (81472048, 81272911 to J.L.; 81330049 to M.L.; 81522011 to J.W.), the Science and Technology Commission of Shanghai Municipality (15140903600 to J.L.), and the Innovation Program of Shanghai Municipal Education Commission (14ZZ051 to J.L.). The advanced ERC grant and an Era of Hope/DoD innovator award were given to JMP. We thank G. Ning (Ruijin Hospital, Shanghai JiaoTong University School of Medicine) for the Lgr4floxed mice, J. Penninger (Institute of Molecular Biotechnology of the Austrian Academy of Sciences) for the Rankfloxed mice, and Y. Zhang (Shanghai East Hospital, Tongji University School of Medicine) for the LysM-Cre mice.

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    • Jian Luo
    •  & Zhengfeng Yang

    These authors contributed equally to this work.


  1. East China Normal University and Shanghai Changzheng Hospital Joint Research Center for Orthopedic Oncology, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.

    • Jian Luo
    • , Zhengfeng Yang
    • , Yu Ma
    • , Zhiying Yue
    • , Hongyu Lin
    • , Guojun Qu
    • , Jinping Huang
    • , Chenghai Li
    • , Chunbing Zheng
    • , Leqin Xu
    • , Huaqing Chen
    • , Dali Li
    • , Jianru Xiao
    •  & Mingyao Liu
  2. Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, Shanghai, China.

    • Wentao Dai
  3. Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

    • Jiqiu Wang
    •  & Guang Ning
  4. Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.

    • Stefan Siwko
    •  & Mingyao Liu
  5. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.

    • Josef M Penninger
  6. Department of Orthopedic Oncology, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai, China.

    • Jianru Xiao


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J.L. and Z. Yang generated the initial idea, proposed the hypothesis, and designed the study. Z.Yang conducted the key experiments. J.L. and M.L. supervised the study and performed the data analysis, interpreted results and wrote the manuscript. Y.M., Z. Yue, H.L., G.Q., J.H., C.L., and C.Z., performed the experiments. W.D. performed the docking and molecular modeling. L.X. and J.X. prepared and analyzed human samples. H.C., J.W., D.L., S.S., J.M.P., and G.N. provided the animals and analyzed the animal data. S.S. and J.M.P., analyzed data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jian Luo or Jianru Xiao or Mingyao Liu.

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