LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption
Abstract
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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The extracellular domain of LGR4 binds RANKL and inhibits NFATC1 expression, blocking osteoclastogenesis.
“The extracellular domain of LGR4 binds RANKL and inhibits NFATC1 expression, thus blocking osteoclastogenesis.172”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [172]
The balance among RANK, RANKL, OPG, and LGR4 fine tunes bone resorption in bone remodeling, and pharmacological modulation of this balance has critical therapeutic potential in osteoporosis.
“The balance achieved among RANK, RANKL, OPG, and LGR4 fine tunes bone resorption in the bone remodeling process, and the pharmacological modulation of this balance has critical therapeutic potential in osteoporosis.172”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [172]
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- Authors
- Luo, J., Yang, Z., Ma, Y., Yue, Z., Lin, H., Qu, G., Huang, J., Dai, W., Li, C., Zheng, C., Xu, L., Chen, H., Wang, J., Li, D., Siwko, S., Penninger, J. M., Ning, G., Xiao, J., & Liu, M.
- Affiliations
- Shanghai Changzheng Hospital (CN)
- Shanghai Academy of Science & Technology (CN)
- Shanghai Jiao Tong University (CN)
- Texas A&M University (US)
- Institute of Molecular Biotechnology (AT)
- Second Military Medical University (CN)
- Corresponding author
- Luo, Jian
- Xiao, Jianru
- Liu, Mingyao
- ORCID
- Venue
- Nature Medicine
- Published
- 2016-04-11
- Volume
- 22
- Issue
- 5
- Pages
- 539-546
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2330722106
- Cited by
- 370
- References
- 45
- Citations by year
- 2026: 21 · 2025: 25 · 2024: 37 · 2023: 38 · 2022: 51 · 2021: 37 · 2020: 47 · 2019: 35 · 2018: 33 · 2017: 36 · 2016: 10
- FWCI
- 19.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- LGR4, RANKL, RANK, osteoclastogenesis, bone resorption, osteoporosis, NFATc1, Gαq signaling, receptor competition, bone erosion
- MeSH terms
- RAW 264.7 Cells, Glycogen Synthase Kinase 3 beta, Animals, Bone Resorption, Calcium, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Humans, Leukocytes, Mononuclear, Osteogenesis, Osteoporosis, Blotting, Western, Signal Transduction, Bone Remodeling, Giant Cell Tumor of Bone, Mice, Knockout, Surface Plasmon Resonance, Receptors, G-Protein-Coupled, GTP-Binding Protein alpha Subunits, Gq-G11, Chromatin Immunoprecipitation, Immunoprecipitation, NFATC Transcription Factors, Mice, RANK Ligand, X-Ray Microtomography, HEK293 Cells, Real-Time Polymerase Chain Reaction, Optical Imaging, Molecular Docking Simulation
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