Figure - available from: Frontiers in Immunology
This content is subject to copyright.
Contribution of the RANKL–RANK axis in immune system and bone metastasis. Among tumor-infiltrating immune cells, the expression of RANKL has been observed on all immune cell types, such CD8+ T, CD4+ T, and Treg cells, and RANKL can act on dendritic cells (DCs) to promote their survival and to prolong T–DC interactions. Bone-resorbing factors, such as vitamin D3, PTHrP, IL-1, IL-11, IL-17, and TNF-α, act on osteoblasts to induce RANKL, which binds to RANK present at the surface of osteoclast progenitors (pre-osteoclasts), which results in bone resorption by mature osteoclasts. The figure was designed using Adobe Illustrator CC.
Source publication
A substantial amount patients with cancer will develop bone metastases, with 70% of metastatic prostate and breast cancer patients harboring bone metastasis. Despite advancements in systemic therapies for advanced cancer, survival remains poor for those with bone metastases. The interaction between bone cells and the immune system contributes to a...
Similar publications
Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue an...
Fibrous dysplasia (FD) is a rare, disabling skeletal disease with no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear Kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated mechanisms underlying RANKL neutralization with the monoclonal antibody d...
Citations
... 14 15 The soluble receptor activator of nuclear factor kappa-B ligand (RANKL) is a cytokine pivotal in bone metabolism and immune regulation. 16 Studies have indicated that RANKL is overexpressed in various cancers, including NSCLC, correlating with tumor progression, metastasis and poor prognosis. [17][18][19] RANKL can directly foster tumor growth and survival by activating the RANK signaling pathway in tumor cells and indirectly bolster tumor immune evasion by modulating the TME and immune responses. ...
... [17][18][19] RANKL can directly foster tumor growth and survival by activating the RANK signaling pathway in tumor cells and indirectly bolster tumor immune evasion by modulating the TME and immune responses. 16 20 21 Furthermore, RANKL can induce PDL1 expression on dendritic cells (DCs) and tumor cells, potentially inhibiting T cell responses and diminishing the efficacy of PD1/PDL1 checkpoint inhibitors. 22 Our group has identified RANKL as a negative predictive biomarker for the efficacy of PD1/PDL1 checkpoint inhibitors in patients with metastatic renal cancer. ...
... 27 28 Notably, RANKL appears to influence the immune system by promoting the differentiation and activation of DCs and T cells, as well as by stimulating PDL1 expression on both tumor and immune cells. 16 Additionally, RANKL can stimulate the secretion of chemokines by M2 macrophages, leading to an increased proliferation of regulatory T cells (TREG). 29 Furthermore, RANKL has been shown to activate the immune regulatory functions of Open access myeloid-derived suppressor cells (MDSCs) and promote the expansion of monocytic MDSCs. ...
Background
Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.
Methods
Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).
Results
The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL’s potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.
Conclusion
These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.
... FAK is a key component of the integrins-mediated signaling pathway. FAK act as a signaling molecule that transduces integrins receptor signaling through the intracellular protein cascade to participate in the adhesion process [36][37][38][39]. The RANK protein plays a crucial role in bone and immune system regulation, making it a key component in the field of bone immunity. ...
... IL-1 induces RANKL expression, which promotes osteoclast differentiation through the production of prostaglandin E in the bone tissue. It also affects bone resorption via an alternative pathway (9)(10)(11). Therefore, natural drugs that downregulate the production of inflammatory cytokines may be useful for the treatment of RA. ...
Rheumatoid arthritis (RA) is an autoimmune and chronic inflammatory disease characterized by articular cartilage destruction, bone destruction and synovial hyperplasia. It has been suggested that Vigeo, a mixture of Eleutherococcus senticosus, Achyranthes japonica and Atractylodes japonica fermented with Korean nuruk, has an anti-osteoporotic effect in a mouse model of inflammation-mediated bone loss. The present study evaluated the therapeutic effects of Vigeo in RA using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen on days 0 and 21 and Vigeo was administered daily for 20 days beginning the day after the second type II collagen injection. The mice were sacrificed on day 42 and the joint tissues were anatomically separated and subjected to micro computed tomography and histological analyses. In addition, the serum levels of TNF-α, IL-6 and IL-1β were determined by enzyme-linked immunosorbent assays. CIA in DBA/1J mice caused symptoms of RA, such as joint inflammation, cartilage destruction and bone erosion. Treatment of CIA mice with Vigeo markedly decreased the symptoms and cartilage pathology. In addition, radiological and histological analyses showed that Vigeo attenuated bone and cartilage destruction. The serum TNF-α, IL-6 and IL-1β levels following oral Vigeo administration were also reduced when compared with those in CIA mice. The present study revealed that Vigeo suppressed arthritis symptoms in a CIA-RA mouse model, including bone loss and serum levels of TNF-α, IL-6 and IL-1β.
... Further clinical trials are required to confirm its in vivo efficacy. Denosumab is employed for its ability to impede the RANK-RANKL pathway, thus influencing the generation of osteoclasts and delaying the onset of skeletal related events caused by bone metastases [72]. Additionally, studies by the CAPIETTO group indicated that combined elimination of granulocytes and osteoclasts was necessary for the removal of established bone allograft metastases of both LLC-Fl cells and 4 T1-Fl cells [73]. ...
Previous studies illustrated that macrophage, a type of innate immune cell, plays critical roles in tumour progression and metastasis. Bone is the most frequent site of metastasis for several cancer types including breast, prostate, and lung. In bone metastasis, osteoclast, a macrophage subset specialized in bone resorption, was heavily investigated in the past. Recent studies illustrated that other macrophage subsets, e.g. monocyte-derived macrophages, and bone resident macrophages, promoted bone metastasis independent of osteoclast function. These novel mechanisms further improved our understanding of macrophage heterogeneity in the context of bone metastasis and illustrated new opportunities for future studies.
... RANKL, as a member of TNFSF, and its receptor, RANK, play important roles in osteogenesis, organization of lymphoid tissues, as well as dendritic cell survival [81]. Dysregulation of the RANKL-RANK axis is involved in numerous inflammatory diseases, including RA. ...
Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses.
... [5,7] Humanized monoclonal antibodies against RANKL, such as denosumab, have been developed to curb bone loss and skeletal-related events (SREs). [8] However, the recent phase 3 D-CARE study reported that denosumab treatment did not significantly improve survival rates for BCBM management. [9] Currently, most BC patients ...
According to recent statistics, breast cancer (BC) has had the highest incidence of newly diagnosed cases worldwide since 2020. Distant metastasis is the primary cause of mortality in BC patients, with bone being the most common BC metastatic site. Unfortunately, there are limited medications available for managing breast cancer bone metastasis (BCBM), and most treatments are palliative. This study aims to investigate the efficacy and mechanism of the Teng Qi Formula in treating bone metastasis in breast cancer. MTS assay and colony formation assay were performed to determine the cytotoxicity of the Teng Qi formula in vitro. The xenograft model was employed to determine the tumor growth inhibition effects of the Teng Qi formula in vivo. A wound healing assay was used to analyze the inhibitory effects of the Teng Qi formula on tumor cell motility. Network pharmacological analysis and western blotting assay were used to explore the underlying mechanisms of the Teng Qi formula's efficacy. Although the Teng Qi formula did not significantly contribute to anti-TNBC cell proliferation and viability, it has been demonstrated that its treatment is significantly associated with the inhibition of tumor cell motility, an extended overall survival time, and bone protection in mice with BCBM. Network pharmacological analysis and western blot were employed to uncover the underlying mechanisms of the Teng Qi formula and its anti-BCBM effects. The "Teng Qi" formula regulates approximately 24 distinct signaling pathways enriched by two different strategies during BCBM treatment. Based on the Western blotting assay, the Teng Qi formula is suggested to prevent EMT, independent of the GSK3β pathways. Teng Qi formula exhibits notable inhibitory effects on tumor cell motility and demonstrates beneficial outcomes such as prolonged overall survival in mice with BCBM. It inhibits the EMT independent of GSK3β pathways makes it beneficial in the treatment of BCBM. In addition, integrated network pharmacological analyses suggest that the regulation of 24 different signaling pathways may be the underlying mechanism of the Teng Qi formula in preventing BCBM. These findings highlight the potential of the Teng Qi formula as a therapeutic option for managing BCBM and provide a foundation for further research and development of this herbal medicine in BC treatment.
... As osteoclast differentiation begins, the RANKL-RANK duet triggers several signal transduction pathways. These include the mitogen-activated protein kinase (MAPK), phosphoinositide-3-kinase/ protein kinase B (PI3K/AKT), and nuclear factor kappa-B (NF-ΚB), which amplify the activity of many pivotal factors like nuclear factor of activated T-cells cytoplasmic 1 (NFATC1) and its downstream genes, including V-ATPase d2 (Atp6v0d2), cathepsin K (CTSK), calcitonin receptor (CTR), and tartrate-resistant acid phosphatase (TRAP) [4][5][6][7]. However, the overzealous indulgence of the osteoclasts (escalating numbers or increased activity) can induce the progression of many osteoclast-related diseases like osteoarthritis, periodontitis, and rheumatoid arthritis. ...
... Osteoclasts are a unique type of mononuclear macrophage cells, mainly derived from hematopoietic stem cell (HSC) progenitors. These mature osteoclasts, differentiated from these osteoclastic precursors, are driven by two classical stimulatory pathways (M-CSF/CSF-1R and RANKL/ RANK) and participate in bone resorption, which is dynamically balanced with the osteogenic capacity of osteoblasts under physiological conditions [1,2,6]. Osteoclasts-related diseases like osteoarthritis and periodontitis arise when the number or the bone resorption capacity of osteoclasts significantly exceeds normal levels. ...
... The MAPK, PI3K-AKT, and NF-κB pathways are three important pathways for osteoclastogenesis [6,7]. Next, we attempted to assess the Chi3l1 function on these pathways in BMMs induced by RANKL, and we found that exogenous Chi3l1 recombinant protein promoted MAPK and AKT pathways in BMMs, albeit to a slightly lesser extent than RANKL. ...
Background
Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated.
Methods
Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis.
Results
Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo.
Conclusions
Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases.
... During the late 1990s, the RANK-RANKL-OPG system was elucidated as a pivotal regulator of bone remodeling [1,2]. Subsequently, its multifaceted role has unfolded, encompassing significant contributions to immune function modulation, lymph node and thymus organogenesis, mammary gland development during pregnancy, thermoregulation, and the control of fever or hair growth [3][4][5][6][7][8]. The expression of RANK and RANKL has also been closely linked to cancer, with more extensive research having been conducted in the context of bone metastasis and breast cancer. ...
The RANK–RANKL–OPG system is a complex signaling pathway that plays a critical role in bone metabolism, mammary epithelial cell development, immune function, and cancer. RANKL is a ligand that binds to RANK, a receptor expressed on osteoclasts, dendritic cells, T cells, and other cells. RANKL signaling promotes osteoclast differentiation and activation, which leads to bone resorption. OPG is a decoy receptor that binds to RANKL and inhibits its signaling. In cancer cells, RANKL expression is often increased, which can lead to increased bone resorption and the development of bone metastases. RANKL-neutralizing antibodies, such as denosumab, have been shown to be effective in the treatment of skeletal-related events, including osteoporosis or bone metastases, and cancer. This review will provide a comprehensive overview of the functions of the RANK–RANKL–OPG system in bone metabolism, mammary epithelial cells, immune function, and cancer, together with the potential therapeutic implications of the RANK–RANKL pathway for cancer management.
... Clinicians should also decide whether the lesions are osteolytic or osteoblastic. In many cases, bone metastatic lesions in lung cancer are osteolytic [23]. Imaging such as MRI can be helpful in this situation. ...
Oligometastases is a term commonly used to describe a disease state characterized by a limited number of distant metastases, and represents a transient phase between localized and widespread systemic diseases. This subgroup of stage IV cancer has increased in clinical importance due to the possibility of curative rather than palliative treatment. Among advanced lung cancer patients, 30-40% show bone metastases, and can show complications such as pathological fractures. Many prospective studies have shown efficacy of localized treatment in oligometastatic non-small cell lung cancer (NSCLC) in improving progression-free survival and overall survival. Compared to metastases in other organs, bone metastases are unique in terms of tumor microenvironment and clinical outcomes. Radiotherapy is the most frequently used treatment modality for local ablative treatment for both primary and metastatic lesions. Stereotactic body radiation therapy demonstrated more rapid and effective pain control compared to conventional 3D conformal radiotherapy. Radiotherapy improved outcomes in terms of time-to-skeletal related events skeletal-related events (SRE), hospitalization for SRE, pain relief, and overall survival in patients with bone metastases. Decision on timing of local ablative treatment depends on patient's overall clinical status, treatment goals, potential side effects of each approach, and expected initial responses to systemic anti-cancer treatment.
... Moreover, OPG, acting as a decoy receptor for RANKL, indirectly inhibits RANK signaling. 67,68 Notably, recent studies have revealed that B cells contribute to a significant portion of OPG production in the bone marrow, accounting for 64% of the total OPG production. This substantial OPG secretion by B cells enables the antagonistic effect of OPG on RANK, thereby impeding osteoclast maturation. ...
Immune homeostasis is delicately mediated by the dynamic balance between effector immune cells and regulatory immune cells. Local deviations from immune homeostasis in the microenvironment of bone fractures, caused by an increased ratio of effector to regulatory cues, can lead to excessive inflammatory conditions and hinder bone regeneration. Therefore, achieving effective and localized immunomodulation of bone fractures is crucial for successful bone regeneration. Recent research has focused on developing localized and specific immunomodulatory strategies using local hydrogel-based delivery systems. In this review, we aim to emphasize the significant role of immune homeostasis in bone regeneration, explore local hydrogel-based delivery systems, discuss emerging trends in immunomodulation for enhancing bone regeneration, and address the limitations of current delivery strategies along with the challenges of clinical translation.
