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The OPG/RANKL/RANK pathway as a therapeutic target. OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-ligand; RANK, receptor activator of nuclear factor-.
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Bone metastases play an important role in the morbidity and mortality of patients with malignant disease. Despite therapeutic advances in the treatment of solid organ malignancy such as lung cancer, less development on metastasis interventions has been forthcoming. More recent research has focused on molecular pathway manipulation in the prevention...
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Background
The receptor activator of NF-κB (RANK), its ligand (RANKL) and osteoprotegerin (OPG) have been reported to play a role in the pathophysiological bone turnover and in the pathogenesis of breast cancer. Based on this we investigated the role of single nucleotide polymorphisms (SNPs) within RANK, RANKL and OPG and their possible association...
An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, mar...
Objective: The study was conducted to evaluate the relation between insulin-like growth factor-1 and osteocalcin and markers of bone modulation (osteoprotegerin; OPG, receptor activator nuclear kappa B; RANK and RANK ligand; RANKL) in postmenopausal Type 2 diabetic women with and without osteoporosis. Methods: The study was conducted on 90 female d...
Citations
... In our study, we identified six signature genes, namely TNFRSF11B, METTL7B, SSTR2, OXTR, CDKN2C, and H19 which have been extensively studied in the past and are known to play a significant role in cancer. TNFRSF11B, also known as osteoprotegerin, is a protein that regulates bone homeostasis and has been shown to play a role in cancer development [64][65][66]. TNFRSF11B activation of the Wnt/βcatenin signaling pathway has been found to promote the progression of gastric cancer [65]. Similarly, METTL7B is critical for cell cycle progression and tumorigenesis in non-small cell lung cancer [67]. ...
Cuprotosis, an emerging mode of cell death, has recently caught the attention of researchers worldwide. However, its impact on low-grade glioma (LGG) patients has not been fully explored. To gain a deeper insight into the relationship between cuprotosis and LGG patients’ prognosis, we conducted this study in which LGG patients were divided into two clusters based on the expression of 18 cuprotosis-related genes. We found that LGG patients in cluster A had better prognosis than those in cluster B. The two clusters also differed in terms of immune cell infiltration and biological functions. Moreover, we identified differentially expressed genes (DEGs) between the two clusters and developed a cuprotosis-related prognostic signature through the least absolute shrinkage and selection operator (LASSO) analysis in the TCGA training cohort. This signature divided LGG patients into high- and low-risk groups, with the high-risk group having significantly shorter overall survival (OS) time than the low-risk group. Its predictive reliability for prognosis in LGG patients was confirmed by the TCGA internal validation cohort, CGGA325 cohort and CGGA693 cohort. Additionally, a nomogram was used to predict the 1-, 3-, and 5-year OS rates of each patient. The analysis of immune checkpoints and tumor mutation burden (TMB) has revealed that individuals belonging to high-risk groups have a greater chance of benefiting from immunotherapy. Functional experiments confirmed that interfering with the signature gene TNFRSF11B inhibited LGG cell proliferation and migration. Overall, this study shed light on the importance of cuprotosis in LGG patient prognosis. The cuprotosis-related prognostic signature is a reliable predictor for patient outcomes and immunotherapeutic response and can help to develop new therapies for LGG.
... The canonical Wnt signaling pathway has been reported crucial roles in bone remodeling and repair. Wnts inhibit osteoclast formation through β-catenin-dependent modulation of OPG/RANKL/RANK system, i.e. the final mediator of osteoclastogenesis [11]. As revealed by recent studies, Wnt signaling may also interact with transforming growth factor-β (TGF-β)/bone morphogenic protein (BMP) signaling on mesenchymal osteoblast progenitors and differentiated osteoblasts during osteoblast differentiation and bone formation [2,12,13]. ...
Wnts are a family of evolutionary-conserved secreted signaling molecules and PI3K-Akt is an intracellular signal transduction. These signaling pathways play significant roles in stromal microenvironment control of the balance between hematopoietic stem cell self-renewal and differentiation. An increasing body of evidence also indicates Wnt and PI3K signaling involvement in the disruption of this balance in hematologic malignancies, where the stromal microenvironment niche favors the infiltration and homing of cancer cells in the bone marrow, as well as leukemia stem cell development and chemoresistance. In the present review, we summarize and discuss the role of the canonical Wnt and PI3K/AKT signaling pathways in normal hematopoiesis and hematologic malignancies, in regards to recent findings on stromal microenvironment involvement in these processes.
... All of the above-mentioned steps are necessary for osteoclast differentiation. High concentrations of OPG result in inhibition of the pathway and thus negatively regulate osteoclast differentiation [39]. 2. Rho is a family of proteins which act in actin polymerization. ...
Bone-related diseases are major contributors to morbidity and mortality in elderly people and the current treatments result in insufficient healing and several complications. One of the promising areas of research for healing bone fractures and skeletal defects is regenerative medicine using stem cells. Differentiating stem cells using agents that shift cell development towards the preferred lineage requires activation of certain intracellular signaling pathways, many of which are known to induce osteogenesis during embryological stages. Imitating embryological bone formation through activation of these signaling pathways has been the focus of many osteogenic studies. Activation of osteogenic signaling can be done by using small molecules. Several of these agents, e.g., statins, metformin, adenosine, and dexamethasone have other clinical uses but have also shown osteogenic capacities. On the other hand, some other molecules such as T63 and tetrahydroquinolines are not as well recognized in the clinic. Osteogenic small molecules exert their effects through the activation of signaling pathways known to be related to osteogenesis. These pathways include more well-known pathways including BMP/Smad, Wnt, and Hedgehog as well as ancillary pathways including estrogen signaling and neuropeptide signaling. In this paper, we review the recent data on small molecule-mediated osteogenic differentiation, possible adjunctive agents with these molecules, and the signaling pathways through which each small molecule exerts its effects.
Graphical Abstract
... Using bioinformatics and combinatorial screening approaches to determine biomarker expression status could be useful in identifying patients who may benefit most from treatment. The RANK/RANKL pathway is often overexpressed and has been positively correlated with tumor progression and advanced disease in primary malignant tumors of the bone, including osteosarcoma, multiple myeloma, and GCTB [16][17][18][19][20]. Moreover, RANK and RANKL expressions are often higher in malignant histological subtypes of bone cancer. ...
The receptor activator of the nuclear factor kappa B ligand (RANKL) is the therapeutic target of denosumab. In this study, we evaluated whether radiomics signature and machine learning analysis can predict RANKL status in spinal giant cell tumors of bone (GCTB). This retrospective study consisted of 107 patients, including a training set (n = 82) and a validation set (n = 25). Kaplan-Meier survival analysis was used to validate the prognostic value of RANKL status. Radiomic feature extraction of three heterogeneous regions (VOIentire, VOIedge, and VOIcore) from pretreatment CT were performed. Followed by feature selection using Selected K Best and least absolute shrinkage and selection operator (LASSO) analysis, three classifiers (random forest (RF), support vector machine, and logistic regression) were used to build models. The area under the curve (AUC), accuracy, F1 score, recall, precision, sensitivity, and specificity were used to evaluate the models’ performance. Classification of 75 patients with eligible follow-up based on RANKL status resulted in a significant difference in progression-free survival (p = 0.035). VOIcore-based RF classifier performs best. Using this model, the AUCs for the training and validation cohorts were 0.880 and 0.766, respectively. In conclusion, a machine learning approach based on CT radiomic features could discriminate prognostically significant RANKL status in spinal GCTB, which may ultimately aid clinical decision-making.
... The mechanisms by which tumor metastasis induces bone destruction have been studied [31]. It is currently believed that metastatic tumor cells directly or indirectly activate the differentiation and maturation of osteoclasts and osteoblasts, resulting in tumor-induced osteoclastic and osteogenic bone destruction [32,33]. Therefore, the present study selected the OPG/RANKL/ RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. ...
Epimedium is a traditional Chinese medicine that is most commonly prescribed by practitioners of Chinese medicine for the clinical treatment of malignant tumor bone metastasis. The main component of Epimedium is icariin (ICA). Studies have shown that ICA inhibits bone resorption of osteoclasts through the OPG/RANKL/RANK signaling pathway. Osteoclasts are the only cells in the body that have a bone-destroying capability. The OPG/RANKL/RANK system consists of cytokines that play major roles in osteoclast formation. Therefore, our study selected the OPG/RANKL/RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. We established the model of bone metastasis in nude mice, intervened the model with icariin and zoledronic acid, and detected the levels of OPG and RANKL by ELISA and western blot. The results showed that ICA had a significant inhibitory effect on bone metastases in nude mice. ICA achieved its antibone metastasis effect in nude mice with lung cancer via inhibiting RANKL expression and simultaneously increasing OPG expression. ICA not only alleviated osteolytic bone destruction caused by bone metastases, but it also reduced weight loss in tumor-bearing nude mice at the late stage of the experiment. The role of ICA in preventing bone metastasis of lung cancer merits further investigation.
... A interação recetor ativador do fator nuclear κ Bligando do recetor ativador do fator nuclear κ B (RANK-RANKL) é importante na regulação da osteoclastogénese, e a inibição dessa interação pode interromper a osteólise e a destruição óssea induzida pelas metástases ósseas 34 . A expressão de RANKL tem sido associada à proliferação de tumores sólidos, porque as células tumorais estimulam a atividade osteoclástica, levando à libertação de fatores de crescimento (como o fator de crescimento tecidual β) que estimulam o crescimento do tumor [34][35][36] . ...
... A interação recetor ativador do fator nuclear κ Bligando do recetor ativador do fator nuclear κ B (RANK-RANKL) é importante na regulação da osteoclastogénese, e a inibição dessa interação pode interromper a osteólise e a destruição óssea induzida pelas metástases ósseas 34 . A expressão de RANKL tem sido associada à proliferação de tumores sólidos, porque as células tumorais estimulam a atividade osteoclástica, levando à libertação de fatores de crescimento (como o fator de crescimento tecidual β) que estimulam o crescimento do tumor [34][35][36] . O denosumab é um inibidor do RANKL e, através da inibição dos osteoclastos, reduz a dor associada ao cancro metastático 4,22 . ...
... Como resultado, o mecanismo de ação do denosumab na dor oncológica metastática é semelhante ao dos bisfosfonatos, pois ambos interferem na atividade osteoclástica. O denosumab também pode suprimir tumores sólidos, através da redução da expressão do RANKL, e consequente redução da libertação de fatores de crescimento, o que pode reduzir o crescimento do tumor 34 . ...
O cancro é um enorme problema de saúde em todo o mundo, com uma prevalência crescente. A dor é uma comorbilidade experienciada de uma forma complexa pelos doentes com lesões metastáticas. Devido à complexidade dos mecanismos envolvidos na génese e manutenção da dor oncológica, a abordagem clássica com a administração de medicamentos opioides parece ser insuficiente
... It is activated by binding to RANKL expressed on the surface of osteoblasts and stromal cells, with the assistance of macrophage-colony stimulating factor (M-CSF) (56). The RANK/RANKL interaction subsequently activates transcription factors, such as NF-kB, and eventually increases the number of activated osteoclasts (57). OPG, a decoy receptor secreted by osteoblasts and stromal cells, inhibits the positive effects of RANKL on osteoclasts by preventing the RANKL/RANK interaction. ...
Lung cancer is the leading cause of cancer-related death worldwide. Bone metastasis, which usually accompanies severe skeletal-related events, is the most common site for tumor distant dissemination and detected in more than one-third of patients with advanced lung cancer. Biopsy and imaging play critical roles in the diagnosis of bone metastasis; however, these approaches are characterized by evident limitations. Recently, studies regarding potential biomarkers in the serum, urine, and tumor tissue, were performed to predict the bone metastases and prognosis in patients with lung cancer. In this review, we summarize the findings of recent clinical research studies on biomarkers detected in samples obtained from patients with lung cancer bone metastasis. These markers include the following: (1) bone resorption-associated markers, such as N-terminal telopeptide (NTx)/C-terminal telopeptide (CTx), C-terminal telopeptide of type I collagen (CTx-I), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), pyridinoline (PYD), and parathyroid hormone related peptide (PTHrP); (2) bone formation-associated markers, including total serum alkaline phosphatase (ALP)/bone specific alkaline phosphatase(BAP), osteopontin (OP), osteocalcin (OS), amino-terminal extension propeptide of type I procollagen/carboxy-terminal extension propeptide of type I procollagen (PICP/PINP); (3) signaling markers, including epidermal growth factor receptor/Kirsten rat sarcoma/anaplastic lymphoma kinase (EGFR/KRAS/ALK), receptor activator of nuclear factor κB ligand/receptor activator of nuclear factor κB/osteoprotegerin (RANKL/RANK/OPG), C-X-C motif chemokine ligand 12/C-X-C motif chemokine receptor 4 (CXCL12/CXCR4), complement component 5a receptor (C5AR); and (4) other potential markers, such as calcium sensing receptor (CASR), bone sialoprotein (BSP), bone morphogenetic protein 2 (BMP2), cytokeratin 19 fragment/carcinoembryonic antigen (CYFRA/CEA), tissue factor, cell-free DNA, long non-coding RNA, and microRNA. The prognostic value of these markers is also investigated. Furthermore, we listed some clinical trials targeting hotspot biomarkers in advanced lung cancer referring for their therapeutic effects.
... Our results are in line with an earlier study showing that higher level of TNFR1 positivity independently predicts favourable outcome in NSCLC, particularly in tumours with no clinically distant metastasis [8]. OPG, also inferring improved prognosis in subgroups, is a soluble cytokine receptor, and a member of the tumour necrosis factor (TNF) receptor superfamily [17]. Interestingly, increased OPG levels did not infer an improved prognosis in adenocarcinomas, but in squamous cell carcinomas. ...
Background:
The development of both chronic obstructive pulmonary disease (COPD) and lung cancer (LC) is influenced by smoking related chronic pulmonary inflammation caused by an excessive innate immune response to smoke exposure. In addition, the smoking induced formation of covalent bonds between the carcinogens and DNA and the accumulation of permanent somatic mutations in critical genes are important in the carcinogenic processes, and can also induce inflammatory responses. How chronic inflammation is mirrored by serum markers in COPD and LC and if these markers reflect prognosis in patients with LC is, however, largely unknown.
Methods:
Serum levels of 18 markers reflecting inflammation, endothelial activation and extracellular matrix remodelling were analysed in 207 patients with non-small lung carcinoma (NSCLC) before surgery and 42 COPD patients. 56% of the LC patients also suffered from COPD. The serum samples were analysed by enzyme immunoassays.
Results:
Serum levels of OPG, PTX3, AXL, ALCAM, sCD163, CD147, CatS and DLL1 were significantly higher in patients with COPD as compared to patients with LC. High sTNFR1 levels were associated with improved progression free survival (PFS) and overall survival (OS) in LC patients with (PFS hazard ratio (HR) 0.49, OS HR 0.33) and without COPD (OS HR 0.30). High levels of OPG were associated with improved PFS (HR 0.17) and OS (HR 0.14) for LC with COPD. CRP was significantly associated with overall survival regardless of COPD status.
Conclusion:
Several markers reflecting inflammation, endothelial activation and extracellular matrix remodelling are elevated in serum from patients with COPD compared to LC patients. Presence of COPD might influence the levels of circulating biomarkers. Some of these markers are also associated with prognosis.
... Consequently, drugs that target osteoclast formation can prevent osteolytic diseases. The RANKL signaling pathway is crucial for osteoclast formation and is an important druggable target for developing therapeutics against pathological diseases of bone loss (Cote, 2015;Tat et al., 2009;McGrath, 2011). In this study, we found that geraniol significantly alleviated the RANKL-induced osteoclast differentiation of RAW264.7 macrophages and CD14+ monocytes. ...
Osteoporotic patients have lower bone mass due to increased bone resorption by osteoclasts. The aim of this study was to investigate the cytotoxic and anti-osteoclastogenic effects of geraniol, a natural monoterpene on human CD14+ monocytes (ex vivo) and murine RAW264.7 macrophages (in vitro) using alamar blue and tartrate resistant acid phosphatase staining respectively. The anti-osteoclastogenic activity of geraniol was further explored by analyzing its effects on actin ring formation and bone resorptive function of osteoclasts. Geraniol significantly (p < 0.001) inhibited osteoclast formation in CD14+ monocytes and RAW264.7 macrophages without cytotoxicity. Moreover, reduced osteoclastogenesis in these cells led to an arrest in actin ring formation and diminished bone resorption. Analysis of underlying molecular mechanisms revealed that geraniol alleviated NF-kB activity, an indispensable upstream modulator of osteoclast formation. Furthermore, expression of key osteoclastogenic genes such as dendritic cell-specific transmembrane protein (DC-STAMP) involved in cell-cell fusion and nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), a master transcription factor essential for osteoclast differentiation was downregulated by geraniol. These observations indicate that inhibition of osteoclast differentiation is presumably one of the pharmacological properties of geraniol.
... In contrast, osteoblasts inhibit osteoclastogenesis by secreting OPG, a decoy receptor for RANKL, to block the binding of RANKL to its receptors on pre-osteoclasts (44). Cancer cells modify the pattern of M-CSF, RANKL and OPG expression in osteoblasts, facilitating cancer cell-associated osteolytic bone metastasis (45). In the present study, human lung adenocarcinoma A549 and CL1-5 cells upregulated M-CSF and RANKL expression yet downregulated OPG expression in osteoblasts, thereby increasing osteoclast differentiation and bone resorption activity. ...
Bone metastasis in lung cancer results in an unfavorable outcome for patients by not only impairing the quality of life, yet also increasing the cancer-related death rates. In the present study, we discuss a novel treatment strategy that may benefit these patients. Human CD14+ monocytes treated with macrophage-colony stimulating factor (M-CSF)/receptor activator of nuclear factor κB ligand (RANKL) differentiated into osteoclasts, whereas syringetin (SGN), a flavonoid derivative found in both grapes and wine, suppressed the osteoclastogenesis in vitro in a dose‑dependent manner. In addition, SGN inhibited osteoclast formation induced by human lung adenocarcinoma A549 and CL1-5 cells. The associated signaling transduction pathway in osteoclastogenesis and SGN inhibition was found to be via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. Blocking AKT and mTOR by respective inhibitors significantly decreased lung adenocarcinoma-mediated osteoclastogenesis. Moreover, SGN regulated the lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts by suppressing the stimulatory effect of lung adenocarcinoma on M-CSF and RANKL production in osteoblasts, and reversing the inhibitory effect of the lung adenocarcinoma on OPG production in osteoblasts. The present study has two novel findings. It is the first to illustrate lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts, leading to osteolytic bone metastasis. It also reveals that SGN, a flavonoid derivative, directly inhibits osteoclastogenesis and reverses lung adenocarcinoma‑mediated osteoclastogenesis. In conclusion, the present study suggests that SGN, a natural compound, prevents and treats bone metastasis in patients with lung cancer.
