ArticleThe Journal of clinical investigation2022
RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers, 1 of them a synthesis that pooled it.
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Who cites it
62 citing papers in PubMed, 1 synthesis or guideline pooled it, 76 citations in OpenAlex.
- Global hotspots and trends in pre-metastatic niche research: a bibliometric analysis(2005-2024).Frontiers in immunology · 2025Pooled it
- Article
- Single-cell and spatial transcriptomics characterisation of RSPO2Journal of orthopaedic translation · 2026Article
- Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis.Cancer biology & medicine · 2026Article
- Article
- The osteoporotic niche as a metabolic sanctuary for breast cancer dormancy and reactivation: A mechanistic perspective.iScience · 2026Review
- Hijacking the bone niche: mechanistic insights into bone metastasis in breast cancer.Bone research · 2026Review
- Recombinant LGR4 extracellular domain attenuates osteoclastogenesis and prevents bone metastasis via RANKL inhibition.Journal of bone oncology · 2026Article
- Applications of micro/nano drug delivery systems in cancer pain management.Bioactive materials · 2026Review
- Regulatory mechanisms of LGR4 on cancer and cancer stem cell properties.Discover oncology · 2026Review
- Subcellular Redistribution of Endomembrane GPR15 Promotes NAD+-Mediated Metabolic Reprogramming and Boosts 5-FU Chemosensitivity in Colorectal Cancer.Cancer research · 2026Article
- Targeting the CCL5/CCR5-PI3K-AKT axis suppresses hepatic stellate cell-induced breast cancer metastasis.Cancer cell international · 2026Article
- The m6Am methyltransferase PCIF1 promotes osteogenic differentiation of mesenchymal stem cells through stabilization of Wnt-related transcripts.PLoS biology · 2026Article
- The Lymphatic-Bone Axis in Cancer Metastasis.Cancers · 2026Review
- Targeting Osteoclastogenesis: Sabutoclax reduces tumor-associated osteolysis and tumor burden within the bone microenvironment.American journal of cancer research · 2026Article
- Cognitive decline and reduced bone mineral density under the bone-brain axis: mechanistic insights and imaging evaluation strategies.Frontiers in aging neuroscience · 2026Review
- Plasma R-spondin 2 levels are associated with the progression of diabetic kidney disease.Frontiers in endocrinology · 2026Article
- Clinicopathological characteristics and prognostic factors of invasive micropapillary carcinoma of the breast.Discover oncology · 2025Article
- Aberrant lipid metabolism reshapes the immune landscape in bone metastasis of nasopharyngeal carcinoma.Journal for immunotherapy of cancer · 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
2 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
27 authors at 9 institutions in 3 countries.
Funding
Abstract
Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. DKK1 directly facilitated OP recruitment through suppression of its receptor LDL receptor-related protein 5 (LRP5) but not LRP6, upregulating Rnasek expression via inhibition of canonical WNT signaling. In clinical samples, RSPO2, LGR4, and DKK1 expression showed a positive correlation with BCa bone metastasis. Furthermore, soluble LGR4 extracellular domain (ECD) protein, acting as a decoy receptor for RSPO2 and RANKL, significantly alleviated bone metastasis and osteolytic lesions in a mouse bone metastasis model. These findings provide unique insights into the functional role of OPs as key components of the premetastatic niche for BCa bone metastasis and identify RSPO2/RANKL-LGR4 signaling as a promising target for inhibiting BCa bone metastasis.
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Registered trials
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.