ArticleNature medicine2016
LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.
Article in Nature medicine, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 212 papers.
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Who cites it
212 citing papers in PubMed, 359 citations in OpenAlex.
- Reprogramming bone homeostasis: The recoupling-oriented framework of bidirectional regulation strategies for osteoporosis.iScience · 2026Review
- Temporal transcriptomic profiling uncovers multilevel suppression of RANKL-driven osteoclast differentiation by 14-3-3ζ.The Journal of biological chemistry · 2026Article
- Neddylation of NFATc1 and Runx2 regulates osteoclast-osteoblast balance and represents a dual-action therapeutic target for postmenopausal osteoporosis.Experimental & molecular medicine · 2026Article
- Sulfated polysaccharides target RANK Lys97 to inhibit osteoclast differentiation and reverse osteoporosis.Nature biomedical engineering · 2026Article
- Recombinant LGR4 extracellular domain attenuates osteoclastogenesis and prevents bone metastasis via RANKL inhibition.Journal of bone oncology · 2026Article
- Regulatory mechanisms of LGR4 on cancer and cancer stem cell properties.Discover oncology · 2026Review
- Erythroferrone Modulates Osteoblast-Osteoclast Crosstalk During Bone Remodeling.bioRxiv : the preprint server for biology · 2026Article
- Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU Chemosensitivity in Colorectal Cancer.Cancer research · 2026Article
- Selenium-Doped Calcium Hydroxide Nanoparticles Inhibit Osteoclasts and Promote Osteogenesis for Osteoporosis Treatment.International journal of nanomedicine · 2026Article
- Article
- A Review of the Mechanisms, Biological Basis, and Active Ingredients of Traditional Chinese Medicine Formulations in Regulating Organ Function to Alleviate Osteoporosis.Endocrine, metabolic & immune disorders drug targets · 2026Review
- Novel bioactive compounds in the treatment of osteoporosis: chemistry-driven discovery from preclinical validation to clinical translation.Frontiers in chemistry · 2026Review
- Management of bone metastases in patients with breast cancer: review of bone-modifying therapy, emerging new agents, and future directions.Frontiers in oncology · 2026Review
- Diabetic Charcot Neuroarthropathy: A Contemporary Review of Molecular and Genetic Markers.Foot & ankle international · 2026Review
- RANK hypomethylation is associated with primary osteoporosis in elderly men in Xinjiang: a case-control study.BMC medical genomics · 2025Article
- Leucine-rich repeat-containing G protein-coupled receptor 4 promotes proliferation, invasion and migration, and inhibits apoptosis in non-small cell lung cancer cells.Oncology letters · 2025Article
- Deficiency of Leucine-Rich Repeat Containing G Protein-Coupled Receptor 4 in Pancreas Reduces β Cell Mass.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Transcriptional regulation of Rankl by Txnip-Ecd in aging and diabetic related osteoporosis.Journal of advanced research · 2025Article
- Generation and Purification of RANKL-Derived Small-Fragment Variants for Osteoclast Inhibition.Pharmaceutics · 2025Article
- Article
152 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 6 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.