ArticleMolecular medicine (Cambridge, Mass.)2021
IL4/IL4R signaling promotes the osteolysis in metastatic bone of CRC through regulating the proliferation of osteoclast precursors.
Article in Molecular medicine (Cambridge, Mass.), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 12 citations in OpenAlex.
- VITAGRAPH: building a knowledge graph for biologically relevant learning tasks.Scientific data · 2026Article
- Cytokine Networks Reprogramming the Osteo-Immune Microenvironment in Cancer Bone Metastasis.Calcified tissue international · 2026Review
- Koumine inhibits osteoclastogenesis and prevents ovariectomy-induced bone loss via suppression of the MAPK signaling pathways.Scientific reports · 2026Article
- Lysosome-dependent cell death reveals a prognostic signature in colorectal cancer via integrated analysis of scRNA-seq and bulk RNA-seq data.Translational cancer research · 2026Article
- The Neuro-Bone Axis in Metastatic Progression: Innervation, Neuro-Immune-Osteoclast Crosstalk, and Therapeutic Opportunities.Biology · 2026Review
- Sex-specific transcriptomic profiling reveals key players in bone loss associated with Alzheimer's disease.GeroScience · 2025Article
- The complexity of immune evasion mechanisms throughout the metastatic cascade.Nature immunology · 2024Review
- Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.International journal of molecular sciences · 2024Review
- Effects of circulating inflammatory proteins on osteoporosis and fractures: evidence from genetic correlation and Mendelian randomization study.Frontiers in endocrinology · 2024Article
- Melittin acupoint injection in attenuating bone erosion in collagen-induced arthritis mice via inhibition of the RANKL/NF-κB signaling pathway.Quantitative imaging in medicine and surgery · 2023Article
- Role of protein phosphorylation in cell signaling, disease, and the intervention therapy.MedComm · 2022Review
- Muscle and Bone Defects in Metastatic Disease.Current osteoporosis reports · 2022Review
- A Review of Signaling Transduction Mechanisms in Osteoclastogenesis Regulation by Autophagy, Inflammation, and Immunity.International journal of molecular sciences · 2022Review
- The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma-Recent Findings and Review.Biomedicines · 2022Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundBone metastasis of colorectal cancer (CRC) often indicates a poor prognosis. Osteolysis can be observed in metastatic sites, implying an aberrant activation of osteoclasts. However, how osteoclastogenesis is regulated in metastatic microenvironment caused by colorectal cancer is still unclear.
methodsIn this study, mice bone metastatic model of CRC was established through injection of MC-38 or CT-26 cells. BrdU assays showed primary CD115 ( +) osteoclast precursors (OCPs) proliferated at the first 2 weeks. Transcriptomic profiling was performed to identify differentially expressing genes and pathways in OCPs indirectly co-cultured with CRC cells
resultsThe expression of IL4Rα was found to be significantly upregulated in OCPs stimulated by tumor conditioned medium (CM). Further investigation indicated that IL-4 signaling regulated proliferation of OPCs through interacting with type I IL4 receptor, and neutrophils were the main source of IL-4 in bone marrow. The proliferation of OCPs can be inhibited in IL4 deficiency mice. In addition, ERK pathway was activated by IL4/IL4R signaling. Ravoxertinib, an ERK antagonists, could significantly prevent bone destruction through inhibiting the proliferation of OCPs.
conclusionOur study indicates the essential role of IL4/IL4R signaling for the proliferation of OCPs in early metastasis of CRC predominantly through activating ERK pathway, which remarkedly impacts the number of osteoclasts in later stage and leads to osteolytic lesions. Moreover, Ravoxertinib could be a new therapeutical target for bone metastasis of CRC.
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