ArticleJournal of cellular biochemistry2011
Interleukin-4 inhibits RANKL-induced NFATc1 expression via STAT6: a novel mechanism mediating its blockade of osteoclastogenesis.
Article in Journal of cellular biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- Cytokine Networks Reprogramming the Osteo-Immune Microenvironment in Cancer Bone Metastasis.Calcified tissue international · 2026Review
- IL-4 Correlates With Bone Mineral Density in Men, and IL-4 Depletion May Drive Bone Loss in Men With HIV.The Journal of infectious diseases · 2026Article
- Mechanisms of osteoclast activation in inflammatory bone loss in rheumatoid arthritis.Nature reviews. Rheumatology · 2026Review
- Photobiomodulation Meets Mechanotransduction: Immune-Stromal Crosstalk in Orthodontic Remodeling.Biomedicines · 2025Review
- Functional roles of immune cells in osteoporosis.Frontiers in immunology · 2025Review
- Causal Associations of the Alterations in Peripheral Blood Immune Cell Characteristics on the Incidence of Osteoporosis: A Bidirectional Mendelian Randomization Study.Therapeutics and clinical risk management · 2025Article
- Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.International journal of molecular sciences · 2024Review
- Investigating mechanical and inflammatory pathological mechanisms in osteoarthritis using MSC-derived osteocyte-like cells in 3D.Frontiers in endocrinology · 2024Article
- Oral microbiota-host interaction: the chief culprit of alveolar bone resorption.Frontiers in immunology · 2024Review
- The effect of cytokines on osteoblasts and osteoclasts in bone remodeling in osteoporosis: a review.Frontiers in immunology · 2023Review
- Photothermal-Controlled Release of IL-4 in IL-4/PDA-Immobilized Black Titanium Dioxide (TiOMaterials (Basel, Switzerland) · 2022Article
- A programmed surface on polyetheretherketone for sequentially dictating osteoimmunomodulation and bone regeneration to achieve ameliorative osseointegration under osteoporotic conditions.Bioactive materials · 2022Article
- Maintaining homeostatic control of periodontal bone tissue.Periodontology 2000 · 2021Review
- Osteocyte-Related Cytokines Regulate Osteoclast Formation and Bone Resorption.International journal of molecular sciences · 2020Review
- Article
- The Role of Osteocytes in Inflammatory Bone Loss.Frontiers in endocrinology · 2019Review
- Bone erosions in rheumatoid arthritis: recent developments in pathogenesis and therapeutic implications.Journal of musculoskeletal & neuronal interactions · 2018Review
- Immunobiology of periprosthetic inflammation and pain following ultra-high-molecular-weight-polyethylene wear debris in the lumbar spine.Expert review of clinical immunology · 2018Review
- Regulation of Osteoclast Differentiation by Cytokine Networks.Immune network · 2018Review
- mTOR inhibition rescues osteopenia in mice with systemic sclerosis.The Journal of experimental medicine · 2015Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Interleukin-4 (IL-4) is an important immune regulatory protein that possesses potent anti-osteoclastogenic properties, and does so via the transcription factor STAT6. Previous studies have shown that IL-4 selectively blocks RANKL-induced activation of NF-κB and mitogen-activated protein kinase (MAPK) pathway molecules, suggesting that the cytokine arrests osteoclastogenesis by blockade of these signaling cascades. However, the fact that the inhibitory effect on these pathways requires prolonged IL-4 pretreatment, and that the cytokine fails to exert an anti-osteoclastogenic effect after short-term pre-exposure of RANKL to osteoclast precursors, suggests that an additional, more immediate mechanism may also be involved. In this study, we found that simultaneous exposure of IL-4 did not alter RANKL-dependent activation of NF-κB or MAPKs, whereas the cytokine did block RANKL-induced nuclear factor activated T cells c1 (NFATc1), a master osteoclastogenic transcription factor. This inhibitory effect of IL-4 required STAT6, consistent with its functional role in osteoclastogenesis. In addition, the cytokine also partially impaired RANKL-stimulated bone resorption. Furthermore, IL-4 suppressed expression of RANKL-induced osteoclast specific genes in a STAT6-dependent manner, but failed to do so when osteoclast precursors were pre-exposed to RANKL. Thus, we provide the first evidence that IL-4 inhibits osteoclast formation by inhibiting RANKL induction of NFATc1 via STAT6 as an early event, in addition to its suppression of other signaling pathways. The inhibitory effect is ultimately regulated at the gene expression transcriptional level.
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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.