المؤلفون: Kazuhiro Yokota

المصدر: Immunological Medicine, Vol 47, Iss 1, Pp 6-11 (2024)

مصطلحات موضوعية: Rheumatoid arthritis, osteoclast, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor alpha, interleukin-6, Immunologic diseases. Allergy, RC581-607

الوصف: AbstractOsteoclasts, derived from the monocyte/macrophage line of bone marrow hematopoietic stem cell progenitors, are the sole bone-resorbing cells of the body. Conventional osteoclast differentiation requires macrophage colony-stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. Rheumatoid arthritis (RA) is the most prevalent systemic autoimmune disease and inflammatory arthritis characterized by bone destruction. Increased levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in the serum and joints, cause excessive bone destruction. We have recently reported that stimulation of human peripheral blood monocytes with TNF-α and IL-6 induces the differentiation of osteoclasts with bone resorption activity. This review presents the functional differences between representative osteoclasts, conventional RANKL-induced osteoclasts, and recently identified proinflammatory cytokine (TNF-α and IL-6)-induced osteoclasts in RA patients. We believe novel pathological osteoclasts associated with RA will be identified, and new therapeutic strategies will be developed to target these osteoclasts and prevent the progression of bone destruction.

وصف الملف: electronic resource

العلاقة: https://doaj.org/toc/2578-5826Test

الوصول الحر: https://doaj.org/article/d901cf414b30444b96f2754593c5a64cTest

المؤلفون: Xin-Ran Xu, Jing-Ling Xu, Lu He, Xian-E Wang, Hong-Ye Lu, Huan-Xin Meng

المصدر: Journal of Dental Sciences, Vol 18, Iss 3, Pp 1125-1133 (2023)

مصطلحات موضوعية: Periodontitis, Type 2 diabetes mellitus, Interleukin 17, Visfatin, Receptor activator of nuclear factor-kappa B ligand, Osteoprotegerin, Dentistry, RK1-715

الوصف: Background/purpose:There is a two-way relationship between periodontitis and type 2 diabetes mellitus. This study aimed to compare the inflammatory states in serum and gingival crevicular fluid (GCF) in periodontitis patients with or without type 2 diabetes mellitus (T2DM) and healthy subjects. Materials and methods: 20 subjects were systematic and periodontal healthy (H group), 40 subjects were with periodontitis (CP group), and other 40 were with periodontitis and type 2 diabetes mellitus (DC group). Fasting blood glucose (FBG) and HbA1c was tested. GCF and serum level of interleukin (IL) −17, visfatin, receptor activator of nuclear factor-kappa B (NF-κB) ligand (RANKL)/osteoprotegerin (OPG) ratio were measured. Results: The GCF volume, total amount of IL-17, vastatin, RANKL/OPG ratio in GCF and their concentrations in serum were higher (P 3 mm. Inflammatory state in GCF was positively correlated to systemic inflammation, and both of them were positively correlated to FBG. Conclusion: Moderate and severe periodontitis aggravated systemic inflammation. T2DM together with periodontitis resulted in more severe systemic inflammation. The positive correlation between the periodontal and systemic inflammation and their association with FBG indicated an inflammatory link between periodontitis and T2DM.

وصف الملف: electronic resource

العلاقة: http://www.sciencedirect.com/science/article/pii/S1991790222002902Test; https://doaj.org/toc/1991-7902Test

الوصول الحر: https://doaj.org/article/04352db77eb5414dbde4a62e99e4f665Test

المؤلفون: Inês Soares de Pinho, Catarina Abreu, Inês Gomes, Sandra Casimiro, Teresa Raquel Pacheco, Rita Teixeira de Sousa, Luís Costa

المصدر: Exploration of Targeted Anti-tumor Therapy, Vol 3, Iss 3, Pp 337-361 (2022)

مصطلحات موضوعية: breast cancer, endocrine therapy, resistance mechanisms, receptor activator of nuclear factor kappa b ligand/receptor activator of nuclear factor kappa b, nuclear factor kappa b, notch, Internal medicine, RC31-1245

الوصف: The most common breast cancer (BC) subtypes are hormone-dependent, being either estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), or both, and altogether comprise the luminal subtype. The mainstay of treatment for luminal BC is endocrine therapy (ET), which includes several agents that act either directly targeting ER action or suppressing estrogen production. Over the years, ET has proven efficacy in reducing mortality and improving clinical outcomes in metastatic and nonmetastatic BC. However, the development of ET resistance promotes cancer survival and progression and hinders the use of endocrine agents. Several mechanisms implicated in endocrine resistance have now been extensively studied. Based on the current clinical and pre-clinical data, the present article briefly reviews the well-established pathways of ET resistance and continues by focusing on the three most recently uncovered pathways, which may mediate resistance to ET, namely receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK), nuclear factor kappa B (NFκB), and Notch. It additionally overviews the evidence underlying the approval of combined therapies to overcome ET resistance in BC, while highlighting the relevance of future studies focusing on putative mediators of ET resistance to uncover new therapeutic options for the disease.

وصف الملف: electronic resource

العلاقة: https://www.explorationpub.com/Journals/etat/Article/100286Test; https://doaj.org/toc/2692-3114Test

الوصول الحر: https://doaj.org/article/11c391338a8c464cb2f3af064d704f1aTest

المؤلفون: Chaekyun Kim

المصدر: International Journal of Molecular Sciences, Vol 24, Iss 20, p 15342 (2023)

مصطلحات موضوعية: bone, osteoclast, macrophage colony-stimulating factor (M-CSF), receptor activator of nuclear factor kappa-B ligand (RANKL), mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinases (ERKs), Biology (General), QH301-705.5, Chemistry, QD1-999

الوصف: Bone homeostasis is regulated by the balanced actions of osteoblasts that form the bone and osteoclasts (OCs) that resorb the bone. Bone-resorbing OCs are differentiated from hematopoietic monocyte/macrophage lineage cells, whereas osteoblasts are derived from mesenchymal progenitors. OC differentiation is induced by two key cytokines, macrophage colony-stimulating factor (M-CSF), a factor essential for the proliferation and survival of the OCs, and receptor activator of nuclear factor kappa-B ligand (RANKL), a factor for responsible for the differentiation of the OCs. Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases, play an essential role in regulating the proliferation, differentiation, and function of OCs. ERKs have been known to play a critical role in the differentiation and activation of OCs. In most cases, ERKs positively regulate OC differentiation and function. However, several reports present conflicting conclusions. Interestingly, the inhibition of OC differentiation by ERK1/2 is observed only in OCs differentiated from RAW 264.7 cells. Therefore, in this review, we summarize the current understanding of the conflicting actions of ERK1/2 in OC differentiation.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1422-0067/24/20/15342Test; https://doaj.org/toc/1661-6596Test; https://doaj.org/toc/1422-0067Test

الوصول الحر: https://doaj.org/article/b6753d0bf94145ba899268c9d0d961bdTest

المؤلفون: Takegami, Norihiko, Akeda, Koji, Yamada, Junichi, Sano, Tomohiko, Murata, Koichiro, Huang, Jenny, Masuda, Koichi, Sudo, Akihiro

المصدر: Arthritis Research & Therapy. 19(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Immunology, Aetiology, 2.1 Biological and endogenous factors, Animals, Humans, Intervertebral Disc, Intervertebral Disc Degeneration, Male, Osteoprotegerin, RANK Ligand, Rats, Rats, Sprague-Dawley, Receptor Activator of Nuclear Factor-kappa B, Signal Transduction, Receptor activator of nuclear factor kappa B, Receptor activator of nuclear factor kappa B ligand, Intervertebral disc, Cartilaginous endplate, Proinflammatory cytokine, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences

الوصف: BackgroundThe receptor activator of NF-κB ligand (RANKL), a member of the TNF ligand superfamily, is known to regulate bone metabolism. The expression of each component of the RANK/RANKL/osteoprotegerin (OPG) system in the intervertebral disc (IVD) has not been examined in detail. The purposes of this study were to examine the expression of the RANK/RANKL/OPG system and to evaluate the function of RANKL in the matrix metabolism of the rat IVD.MethodsSprague-Dawley, 12-week-old, male rats were used in this study. Anulus fibrosus (AF), nucleus pulposus (NP) and cartilaginous endplate (CEP) cells isolated from dissected thoracolumbar discs were monolayer-cultured. RANK/RANKL/OPG expression in rat IVDs was examined using real-time polymerase chain reaction (PCR) and immunohistochemical analysis (cultured cells and IVD tissues). To examine the effect of interleukin-1β (IL-1β) stimulation on the mRNA levels of RANK, RANKL and OPG, the cells were cultured with or without recombinant human IL-1β (rhIL-1β). To evaluate the effect of RANKL on the mRNA expression of catabolic factors (IL-1β, matrix metalloproteinase-3 (MMP-3) and MMP-13), the cells were cultured with RANKL in the presence or absence of rhIL-1β. The immunohistochemical expression of this system was also evaluated using human IVD tissues with different grades of degeneration.ResultsmRNA expression levels of RANK, RANKL, and OPG were clearly identified in AF, NP and CEP cells. Immunoreactivity to RANK, RANKL and OPG was distributed in the cell membranes and/or cytoplasm of the three types of cells. The mRNA level of RANKL was significantly upregulated by treatment with rhIL-1β of the three types of cells. Treatment with RANKL without rhIL-1β did not induce significant effects on the mRNA expression of catabolic factors by AF, NP and CEP cells. However, the expression was significantly upregulated by stimulation with RANKL in the presence of rhIL-1β. There was a general trend for more RANK/RANKL/OPG-positive cells in human IVD tissues in an advanced stage of degeneration compared to an early stage.ConclusionsOur study showed the possibility that the RANK/RANKL/OPG system may play a part in the process of intervertebral disc degeneration.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/69c3s0v1Test

المؤلفون: Vidula, Neelima, Yau, Christina, Li, Jiali, Esserman, Laura J, Rugo, Hope S

المصدر: Breast Cancer Research and Treatment. 165(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Cancer, Detection, screening and diagnosis, 4.1 Discovery and preclinical testing of markers and technologies, 2.1 Biological and endogenous factors, Aetiology, Biomarkers, Tumor, Bone Neoplasms, Breast Neoplasms, Chemotherapy, Adjuvant, Disease-Free Survival, Female, Gene Expression Profiling, Humans, Logistic Models, Mastectomy, Middle Aged, Multivariate Analysis, Neoadjuvant Therapy, Neoplasm Recurrence, Local, Oligonucleotide Array Sequence Analysis, Osteoprotegerin, Proportional Hazards Models, RANK Ligand, Radiotherapy, Adjuvant, Receptor Activator of Nuclear Factor-kappa B, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Receptor activator of nuclear factor kappa B, RANK ligand, Bone metastases, Breast cancer, Recurrence-free survival, Clinical Sciences, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis

الوصف: PurposeThe receptor activator of nuclear factor kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) axis may contribute to the development of bone metastases (BM). We studied gene expression in this pathway in primary breast cancer (BC) to determine correlations with clinical characteristics and outcomes in the neoadjuvant I-SPY1 study.MethodsWe evaluated RANK/RANKL/OPG expression using expression microarrays in I-SPY1 (n = 149). Associations with clinical features were determined using t test and ANOVA. Associations between biomarker high versus low groups (dichotomized at an optimal cutpoint) and recurrence-free survival (RFS) were evaluated using the log-rank test and in a multivariate Cox proportional hazard model. A pooled external neoadjuvant cohort with gene expression data (GSE25066) (Hatzis et al. in JAMA 305(18):1873-1881, 30) (n = 425) was used for validation. Associations with site-specific relapse were evaluated using the t-test and multivariate logistic regression adjusting for hormone receptor (HR) status.ResultsRANK was significantly higher in HR negative versus HR positive (p = 0.027), in basal versus non-basal disease (p = 0.004), and in those achieving pathologic complete response (p = 0.038); the associations with HR negative and basal BC were also significant in GSE25066. In both datasets, higher RANK associated with significantly worse RFS (I-SPY1: p = 0.045, GSE25066: p = 0.044). However, this association did not remain significant after adjusting for HR status. In I-SPY1 patients with recurrence, higher RANK correlated with BM versus non-BM (p = 0.045), even after adjusting for HR status (p = 0.035).ConclusionsRANK is increased in HR negative and basal BC, and correlates with worse RFS and risk of BM. The RANK pathway is a potential therapeutic target in BC.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4zc4z1xqTest

المؤلفون: Su, Maureen A, Anderson, Mark S

المصدر: Cancer Immunology Research. 7(6)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Vaccine Related, Autoimmune Disease, Immunization, Cancer, Biotechnology, Animals, Autoimmune Diseases, Autoimmunity, Central Tolerance, Clonal Deletion, Humans, Immunomodulation, Immunotherapy, Molecular Targeted Therapy, Neoplasms, Organ Specificity, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B, T-Lymphocytes, T-Lymphocytes, Regulatory, Thymus Gland, Transcription Factors, Pharmacology and Pharmaceutical Sciences, Oncology and carcinogenesis

الوصف: A major breakthrough in cancer treatment occurred with the development of strategies that overcome T-cell tolerance toward tumor cells. These approaches enhance antitumor immunity by overcoming mechanisms that are normally in place to prevent autoimmunity but simultaneously prevent rejection of tumor cells. Although tolerance mechanisms that restrict antitumor immunity take place both in the thymus and periphery, only immunotherapies that target peripheral tolerance mechanisms occurring outside of the thymus are currently available. We review here recent gains in our understanding of how thymic tolerance mediated by the autoimmune regulator (Aire) impedes antitumor immunity. It is now clear that transient depletion of Aire-expressing cells in the thymus can be achieved with RANKL blockade. Finally, we discuss key findings that support the repurposing of anti-RANKL as a cancer immunotherapy with a unique mechanism of action.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/1980x1bqTest

المؤلفون: Ciscar, M, Trinidad, EM, Perez-Chacon, G, Alsaleem, M, Jimenez, M, Jimenez-Santos, MJ, Perez-Montoyo, H, Sanz-Moreno, A, Vethencourt, A, Toss, M, Petit, A, Soler-Monso, MT, Lopez, V, Gomez-Miragaya, J, Gomez-Aleza, C, Dobrolecki, LE, Lewis, MT, Bruna, A, Mouron, S, Quintela-Fandino, M, Al-Shahrour, F, Martinez-Aranda, A, Sierra, A, Green, AR, Rakha, E, Gonzalez-Suarez, E

المساهمون: Bruna Cabot, Alejandra

مصطلحات موضوعية: ER negative breast cancer, RANK-RANKL, breast cancer patient-derived xenografts, menopause, pharmacological RANKL inhibitors, Female, Humans, Breast Neoplasms, Denosumab, Receptor Activator of Nuclear Factor-kappa B, Postmenopause, RANK Ligand, Signal Transduction

جغرافية الموضوع: England

الوصف: Despite strong preclinical data, the therapeutic benefit of the RANKL inhibitor, denosumab, in breast cancer patients, beyond the bone, is unclear. Aiming to select patients who may benefit from denosumab, we hereby analyzed RANK and RANKL protein expression in more than 2,000 breast tumors (777 estrogen receptor-negative, ER- ) from four independent cohorts. RANK protein expression was more frequent in ER- tumors, where it associated with poor outcome and poor response to chemotherapy. In ER- breast cancer patient-derived orthoxenografts (PDXs), RANKL inhibition reduced tumor cell proliferation and stemness, regulated tumor immunity and metabolism, and improved response to chemotherapy. Intriguingly, tumor RANK protein expression associated with poor prognosis in postmenopausal breast cancer patients, activation of NFKB signaling, and modulation of immune and metabolic pathways, suggesting that RANK signaling increases after menopause. Our results demonstrate that RANK protein expression is an independent biomarker of poor prognosis in postmenopausal and ER- breast cancer patients and support the therapeutic benefit of RANK pathway inhibitors, such as denosumab, in breast cancer patients with RANK+ ER- tumors after menopause.

وصف الملف: Print-Electronic; application/pdf

العلاقة: EMBO Molecular Medicine, 2023, 15 (4), pp. e16715 -; https://repository.icr.ac.uk/handle/internal/5817Test

الإتاحة: https://doi.org/10.15252/emmm.202216715Test
https://repository.icr.ac.uk/handle/internal/5817Test

المؤلفون: Kazuhiro Yokota

المصدر: Immunological Medicine, Pp 1-6 (2023)

مصطلحات موضوعية: Rheumatoid arthritis, osteoclast, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor alpha, interleukin-6, Immunologic diseases. Allergy, RC581-607

الوصف: Osteoclasts, derived from the monocyte/macrophage line of bone marrow hematopoietic stem cell progenitors, are the sole bone-resorbing cells of the body. Conventional osteoclast differentiation requires macrophage colony-stimulating factor and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. Rheumatoid arthritis (RA) is the most prevalent systemic autoimmune disease and inflammatory arthritis characterized by bone destruction. Increased levels of proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), in the serum and joints, cause excessive bone destruction. We have recently reported that stimulation of human peripheral blood monocytes with TNF-α and IL-6 induces the differentiation of osteoclasts with bone resorption activity. This review presents the functional differences between representative osteoclasts, conventional RANKL-induced osteoclasts, and recently identified proinflammatory cytokine (TNF-α and IL-6)-induced osteoclasts in RA patients. We believe novel pathological osteoclasts associated with RA will be identified, and new therapeutic strategies will be developed to target these osteoclasts and prevent the progression of bone destruction.

العلاقة: https://doaj.org/toc/2578-5826Test; https://doaj.org/article/d901cf414b30444b96f2754593c5a64cTest

الإتاحة: https://doi.org/10.1080/25785826.2023.2220931Test
https://doaj.org/article/d901cf414b30444b96f2754593c5a64cTest

المؤلفون: Brouns, Anita J. W. M., Hendriks, Lizza E. L., Robbesom-van den Berge, Iris J., Driessen, Annemariek J. H. M., Roemen, Guido M. J. M., van Herpen, Britt L. . J., Dekkers, Zoe, Heitzer, Bas, Leunissen, Daphne J. G., Moonen, Laura, Lunde, Ragnar, Westenend, Marcel, van Driel, Marjolein, Speel, Ernst-Jan M., Dingemans, Anne-Marie C.

المصدر: Brouns , A J W M , Hendriks , L E L , Robbesom-van den Berge , I J , Driessen , A J H M , Roemen , G M J M , van Herpen , B L J , Dekkers , Z , Heitzer , B , Leunissen , D J G , Moonen , L , Lunde , R , Westenend , M , van Driel , M , Speel , E-J M & Dingemans , A-M C 2023 , ' Association of RANKL and EGFR gene expression with bone metastases in patients with metastatic non-small ....

مصطلحات موضوعية: bone metastases, receptor activator of nuclear factor kappa b ligand, epidermal growth factor expression, osteoprotegerin, lung adenocarcinoma, epidermal growth factor mutation, GROWTH-FACTOR RECEPTOR, MIGRATION, MUTATION, PROTEIN

الوصف: Introduction: Bone metastases are frequent in patients with non-small cell lung cancer (NSCLC). The receptor activator of Nuclear Factor ?B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway is important in bone metastases development. Furthermore, epidermal growth factor receptor (EGFR) signaling promotes osteoclast formation and stimulation. The understanding of the biological mechanism of bone metastases development might have implications for treatment strategies. Therefore, we studied whether there is an association between EGFR, RANKL, RANK and OPG gene expression in the tumor and presence of bone metastases in patients with NSCLC.Methods: From an updated multicenter study, including patients with EGFR mutated (EGFR+), Kirsten rat sarcoma (KRAS+) and EGFR/KRAS wildtype metastatic NSCLC, all patients with available formalin-fixed paraffin-embedded (FFPE) tumor samples were selected. Ribonucleic Acid (RNA) was isolated from these samples and gene expressions of EGFR, RANKL, OPG and RANKL were determined via quantitative Polymerase Chain Reaction (qPCR). Data on demographics, histology and molecular subtyping, sample origin, presence of bone metastasis, SREs and bone progression were collected. Primary endpoint was relation between EGFR, RANK, RANKL, OPG gene expression, RANKL: OPG ratio and bone metastases.Results: In 73/335 (32% EGFR+, 49% KRAS+, 19% EGFR/KRAS wildtype) samples from unique patients, gene expression analysis could be performed. Of these 73 patients, 46 (63%) had bone metastases at diagnosis or developed bone metastases during the disease course. No association was found between EGFR expression and presence of bone metastases. Patients with bone metastases had a significantly higher RANKL expression and RANKL: OPG ratio compared to those without. An increased RANKL: OPG ratio resulted in a 1.65x increased risk to develop bone metastases, especially in the first 450 days after diagnosis of metastatic NSCLC.Conclusion: Increased RANKL gene expression and RANKL: OPG ratio, but not EGFR ...

العلاقة: https://cris.maastrichtuniversity.nl/en/publications/acf8ef45-4992-4031-9397-f2cc868be7c7Test

الإتاحة: https://doi.org/10.3389/fonc.2023.1145001Test
https://cris.maastrichtuniversity.nl/en/publications/acf8ef45-4992-4031-9397-f2cc868be7c7Test