Journal articles: 'RANKL'

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Stejskal, David, Josef Bartek, Radmila Pastorkova, Viktor Ruzicka, Ivo Oral, and Dalimil Horalik. "OSTEOPROTEGERIN, RANK, RANKL." Biomedical Papers 145, no. 2 (December 1, 2001): 61–64. http://dx.doi.org/10.5507/bp.2001.013.

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Nagy, Vanja, and Josef M. Penninger. "The RANKL-RANK Story." Gerontology 61, no. 6 (2015): 534–42. http://dx.doi.org/10.1159/000371845.

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Sale, Craig, David C. Hughes, Julie P. Greeves, Trent Stellingwerff, Craig Ranson, William D. Fraser, and Ian Varley. "Rankl/rank/opg Pathway." Medicine & Science in Sports & Exercise 46 (May 2014): 268. http://dx.doi.org/10.1249/01.mss.0000493990.33112.e2.

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Hanada, Reiko, Toshikatsu Hanada, Verena Sigl, Daniel Schramek, and Josef M. Penninger. "RANKL/RANK—beyond bones." Journal of Molecular Medicine 89, no. 7 (March 29, 2011): 647–56. http://dx.doi.org/10.1007/s00109-011-0749-z.

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Boyce, Brendan F., and Lianping Xing. "The RANKL/RANK/OPG pathway." Current Osteoporosis Reports 5, no. 3 (September 2007): 98–104. http://dx.doi.org/10.1007/s11914-007-0024-y.

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Hofbauer, L. C. "Bedeutung des RANK/RANKL/OPGSignalwegs für den Knochenstoffwechsel." Osteologie 19, no. 04 (2010): 354–57. http://dx.doi.org/10.1055/s-0037-1619956.

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ZusammenfassungDie meisten Knochenstoffwechselkrankheiten sind nach heutigem Kenntnisstand Folge einer gesteigerten Knochenresorption durch Osteoklasten. In den letzten 15 Jahren wurden die entscheidenden molekularen und zellulären Regulatoren der Zellbiologie von Osteoklasten entschlüsselt. Receptor activator of NF-κB-Ligand (RANKL) und sein Rezeptor RANK sind essenziell für die Differenzierung und Aktivierung von Osteoklasten und für eine normale Knochenresorption absolut erforderlich. Die Wirkungen von RANKL werden durch den endogenen löslichen Rezeptorantagonisten Osteoprotegerin (OPG) neutralisiert. Die Balance zwischen RANKL und OPG ist im Östrogenmangel oder bei systemischer Glukokortikoidtherapie gestört und dadurch wird der RANKL/OPG-Quotient erhöht, was zum beschleunigten Knochenverlust führt. Angesichts der fundamentalen Rolle des RANKL/RANK/OPG-Signalwegs im Knochenstoffwechsel ist mittlerweile RANKL zum therapeutischen Target geworden. Strategien der RANKL-Blockade wurden in verschiedenen Tiermodellen klinisch relevanter Knochenerkrankungen erfolgreich eingesetzt. Dazu zählen verschiedene Osteoporoseformen sowie Knochenverlust infolge systemischer Entzündung und Tumoren.

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Hooshiar, Saeedeh Hosseini, Mohammad Tobeiha, and Sadegh Jafarnejad. "Soy Isoflavones and Bone Health: Focus on the RANKL/RANK/OPG Pathway." BioMed Research International 2022 (October 25, 2022): 1–10. http://dx.doi.org/10.1155/2022/8862278.

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Bone remodels via resorption and formation, two phenomena that continuously occur in bone turnover. The RANKL/RANK/OPG pathway is one of the several mechanisms that affect bone turnover. The RANKL/OPG ratio has a substantial role in bone resorption. An imbalance between formation and resorption is related to an increased RANKL/OPG balance. OPG, a member of this system, can bind to RANKL and suppress RANK-RANKL interaction, and subsequently, inhibit further osteoclastogenesis. The serum levels of RANKL and OPG in the bone microenvironment are vital for osteoclasts formation. The RANK/RANKL/OPG system plays a role in the pathogenesis of bone disorders. This system can be considered a new treatment target for bone disorders. Soy isoflavones affect the RANK/RANKL/OPG system through numerous mechanisms. Soy isoflavones decrease RANKL levels and increase OPG levels. Therefore, isoflavones improve bone metabolism and decrease bone resorption. Soy isoflavones decrease serum markers of bone resorption and improve bone metabolism. However, while the available data are promising, the results of several studies reported no change in RANKL and OPG levels with isoflavones supplementation. In this regard, current evidence is insufficient for conclusive approval of the efficacy of isoflavones on RANKL/RANK/OPG and further research, including animal and human studies, are needed to confirm the effect of soy isoflavones on the RANKL/RANK/OPG pathway. This study was a review of available evidence to determine the role of isoflavones in bone hemostasis and the RANK/RANKL/OPG pathway. The identification of the effects of isoflavones on the RANKL/RANK/OPG pathway directs future studies and leads to the development of effective treatment strategies for bone disorders.

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Aslan, Figen, and Ülkü Küçük. "RANK and RANKL Expression in Salivary Gland Tumors." Ear, Nose & Throat Journal 99, no. 7 (June 11, 2020): 475–80. http://dx.doi.org/10.1177/0145561320930640.

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Objectives: The pathogenesis and molecular basis of salivary gland tumors (SGT) are not well understood. We investigated the expression of receptor activator of nuclear factor κB (RANK) and RANK ligand (RANKL) in benign and malignant SGTs and their relationship with clinicopathological features. Methods: Fifty malignant and 38 benign SGTs were analyzed in this study. We evaluated the correlation between RANK and RANKL expression and benign and malignant tumors, as well as the correlation between clinicopathological prognostic parameters and RANK and RANKL expression. Results: Receptor activator of nuclear factor κB was positive in 82% (41) malignant SGTs and in 34.2% (13) benign SGTs. Receptor activator of nuclear factor κB ligand was expressed in 28% (14) malignant and 5.3% (2) benign tumors. Receptor activator of nuclear factor κB and RANKL expression were significantly different between benign and malignant SGTs ( P < .001, P = .006, respectively). However, a relationship was not found between positive expression of RANK or RANKL and clinicopathological features. Conclusions: In our study, RANK and RANKL expression was found to be higher in malignant SGTs compared to benign SGTs and RANK was more sensitive than RANKL. In addition, RANK and RANKL expression was higher in some malignant histological subtypes. Based on these results, we think that RANK and RANKL expression in SGTs and its potential as a target for treatment should continue to be investigated.

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Xing, Lianping, Edward M. Schwarz, and Brendan F. Boyce. "Osteoclast precursors, RANKL/RANK, and immunology." Immunological Reviews 208, no. 1 (December 2005): 19–29. http://dx.doi.org/10.1111/j.0105-2896.2005.00336.x.

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Boyce, Brendan F., and Lianping Xing. "Biology of RANK, RANKL, and osteoprotegerin." Arthritis Research & Therapy 9, Suppl 1 (2007): S1. http://dx.doi.org/10.1186/ar2165.

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Khosla, Sundeep. "Minireview: The OPG/RANKL/RANK System." Endocrinology 142, no. 12 (December 2001): 5050–55. http://dx.doi.org/10.1210/endo.142.12.8536.

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Ohtaka, Mari, Takashi Kawahara, Taku Mochizuki, Daiji Takamoto, Yusuke Hattori, Jun-ichi Teranishi, Yasuhide Miyoshi, et al. "RANK/RANKL expression in prostate cancer." International Journal of Surgery Case Reports 30 (2017): 106–7. http://dx.doi.org/10.1016/j.ijscr.2016.11.042.

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Jang, Yuria, Hong Moon Sohn, Young Jong Ko, Hoon Hyun, and Wonbong Lim. "Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL." International Journal of Molecular Sciences 22, no. 1 (January 4, 2021): 434. http://dx.doi.org/10.3390/ijms22010434.

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Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.

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Ikhena, Deborah E., Shimeng Liu, Stacy Kujawa, Ecem Esencan, John S. Coon, Jared Robins, Serdar E. Bulun, and Ping Yin. "RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth." Journal of Clinical Endocrinology & Metabolism 103, no. 5 (March 14, 2018): 1842–49. http://dx.doi.org/10.1210/jc.2017-01585.

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Abstract Context Uterine leiomyomas are the most common type of gynecologic tumor in women. Objective To determine the role of the cytokine receptor activator of nuclear factor κ-Β ligand (RANKL); its receptor, receptor activator of nuclear factor κ-Β (RANK); and the RANKL/RANK pathway inhibitor RANK-Fc in leiomyoma growth. Design Messenger RNA (mRNA) or protein levels of RANKL, RANK, and proliferation markers cyclin D1 and Ki67 were assessed in various leiomyoma tissues and cell populations. Human xenograft experiments were performed to determine the effects of RANK-Fc on leiomyoma growth in vivo. Setting Research laboratory. Patients Twenty-four regularly cycling premenopausal women (age 28 to 49 years) who were not receiving hormone therapy. Interventions None. Main Outcome Measure Tumor growth in a murine xenograft model following targeting of the RANKL/RANK pathway with RANK-Fc. Results RANKL mRNA levels in leiomyoma were significantly higher than those in myometrial tissues. The highest RANK levels were found in the leiomyoma stem cell population, which is deficient in progesterone receptor (PR). Conversely, the highest RANKL levels were found in the PR-rich leiomyoma intermediate cell (LIC) population. R5020, a PR agonist, specifically increased RANKL expression in LICs. RANK-Fc blocked RANKL-induced expression of the proliferative gene cyclin D1. Treatment with RANK-Fc also significantly decreased tumor growth in vivo and diminished the expression of proliferation marker Ki67 in tumors (P < 0.01; n = 4). Conclusions Treatment with the RANKL/RANK pathway inhibitor RANK-Fc significantly decreased human leiomyoma cell proliferation and tumor growth. This suggests that the RANKL/RANK pathway could serve as a potential target for the prevention and treatment of uterine leiomyoma.

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Xu, Huanhuan, Fei Chen, Titi Liu, Jing Xu, Jin Li, Li Jiang, Xuanjun Wang, and Jun Sheng. "Ellagic acid blocks RANKL–RANK interaction and suppresses RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways." Chemico-Biological Interactions 331 (November 2020): 109235. http://dx.doi.org/10.1016/j.cbi.2020.109235.

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Casimiro, Sandra, Guilherme Vilhais, Inês Gomes, and Luis Costa. "The Roadmap of RANKL/RANK Pathway in Cancer." Cells 10, no. 8 (August 4, 2021): 1978. http://dx.doi.org/10.3390/cells10081978.

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The receptor activator of the nuclear factor-κB ligand (RANKL)/RANK signaling pathway was identified in the late 1990s and is the key mediator of bone remodeling. Targeting RANKL with the antibody denosumab is part of the standard of care for bone loss diseases, including bone metastases (BM). Over the last decade, evidence has implicated RANKL/RANK pathway in hormone and HER2-driven breast carcinogenesis and in the acquisition of molecular and phenotypic traits associated with breast cancer (BCa) aggressiveness and poor prognosis. This marked a new era in the research of the therapeutic use of RANKL inhibition in BCa. RANKL/RANK pathway is also an important immune mediator, with anti-RANKL therapy recently linked to improved response to immunotherapy in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). This review summarizes and discusses the pre-clinical and clinical evidence of the relevance of the RANKL/RANK pathway in cancer biology and therapeutics, focusing on bone metastatic disease, BCa onset and progression, and immune modulation.

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Ikeda, Tohru, Michiyuki Kasai, Masanori Utsuyama, and Katsuiku Hirokawa. "Determination of Three Isoforms of the Receptor Activator of Nuclear Factor-κΒ Ligand and Their Differential Expression in Bone and Thymus*." Endocrinology 142, no. 4 (April 1, 2001): 1419–26. http://dx.doi.org/10.1210/endo.142.4.8070.

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Abstract The receptor activator of nuclear factor (NF)-κB ligand [RANKL; also known as tumor necrosis factor-related activation-induced cytokine, osteoprotegerin ligand, and osteoclast differentiation factor] is known to bind with the receptor activator of NF-κB (RANK) and act not only as a key factor for osteoclastogenesis but also as a regulator of lymphocyte development. In this study, we found two additional isoforms of RANKL. RANKL 2 has a shorter intracellular domain than the original RANKL (RANKL 1), and RANKL 3 lacks a transmembrane domain and was thought to act as a soluble form. In the bone marrow stromal cell line ST2 and preosteoblastic cell line MC3T3-E1, all three RANKL isoforms were detected, but the expression of RANKL 2 was preferentially suppressed by treatment with 1α,25-dihydroxyvitamin D3 and dexamethasone. In young adult thymus, CD4−CD8− double-negative cells were positive for all three isoforms, CD4+CD8+ double-positive cells were positive for RANKL 1 and RANKL 3 but negative for RANKL 2, and CD4+CD8− and CD4−CD8+ single-positive cells were positive for all three isoforms. Immunofluorescence analyses of NIH3T3 cells transfected with each RANKL isoform indicated that the three RANKL isoforms were translated, and RANKL 2 protein predominantly stayed in the endoplasmic reticulum and Golgi networks. These results indicate that there are three kinds of RANKL-RANK pathways. The presence of multiple RANKL-RANK pathways suggests a more complicated RANKL-RANK system for osteoclastogenesis or T cell differentiation than previously thought.

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Woźniczka, Magdalena, and Katarzyna Błaszczak-Świątkiewicz. "New Generation of Meso and Antiprogestins (SPRMs) into the Osteoporosis Approach." Molecules 26, no. 21 (October 27, 2021): 6491. http://dx.doi.org/10.3390/molecules26216491.

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Receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) play key roles in bone metabolism and the immune system. The RANK/RANKL complex has also been shown to be critical in the formation of mammary epithelia cells. The female hormones estradiol and progesterone closely control the action of RANKL with RANK. Blood concentration of these sex hormones in the postmenopausal period leads to an increase in RANK/RANKL signaling and are a major cause of women’s osteoporosis, characterized by altered bone mineralization. Knowledge of the biochemical relationships between hormones and RANK/RANKL signaling provides the opportunity to design novel therapeutic agents to inhibit bone loss, based on the anti-RANKL treatment and inhibition of its interaction with the RANK receptor. The new generation of both anti- and mesoprogestins that inhibit the NF-κB-cyclin D1 axis and blocks the binding of RANKL to RANK can be considered as a potential source of new RANK receptor ligands with anti-RANKL function, which may provide a new perspective into osteoporosis treatment itself as well as limit the osteoporosis rise during breast cancer metastasis to the bone.

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Lovšin, Nika, and Janja Marc. "Glucocorticoid Receptor Regulates TNFSF11 Transcription by Binding to Glucocorticoid Responsive Element in TNFSF11 Proximal Promoter Region." International Journal of Molecular Sciences 22, no. 3 (January 21, 2021): 1054. http://dx.doi.org/10.3390/ijms22031054.

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Glucocorticoid osteoporosis is a serious side effect of long term glucocorticoid uptake and it is caused by osteoblast apoptosis and imbalance in the major bone remodeling pathway RANK/RANKL/OPG. The impact of glucocorticoid on the maintenance of RANK/RANKL/OPG is well explored; dexamethasone was shown to disturb the ratio between OPG and RANKL level by decreasing the expression level of OPG and increasing level of RANKL. Here, were aimed to decipher whether glucocorticoid receptor directly influences RANKL promoter activity and its transcriptional regulation. We demonstrate that overexpression of glucocorticoid receptor (GR) NR3C1 increased RANKL promoter activity in human osteosarcoma, cervical cancer (2-fold) and adenocarcinoma cells (4.5-fold). Mutational analysis revealed that +352 site in the RANKL promoter is functional glucocorticoid responsive element (GRE) since the effect of GR on RANKL promoter activity was diminished by mutation at this site. Overexpression of NR3C1 upregulated RANKL mRNA expression 1.5-fold in human A549 and HOS cells. On the other hand silencing of NR3C1 caused slight decrease in RANKL mRNA level, suggesting that NR3C1 directly accounts for RANKL transcriptional regulation. Using electrophoretic mobility shift assay we demonstrate that NR3C1 binds to the proximal RANKL promoter region. Our study provides evidences that NR3C1 directly upregulates RANKL transcription in human cell lines and connects the missing link in the mechanism of RANK/RANKL/OPG imbalance of glucocorticoid induced osteoporosis.

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van Dam, Peter A., Yannick Verhoeven, Julie Jacobs, An Wouters, Wiebren Tjalma, Filip Lardon, Tim Van den Wyngaert, et al. "RANK-RANKL Signaling in Cancer of the Uterine Cervix: A Review." International Journal of Molecular Sciences 20, no. 9 (May 2, 2019): 2183. http://dx.doi.org/10.3390/ijms20092183.

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RANK ligand (RANKL) is a member of the tumor necrosis factor alpha superfamily of cytokines. It is the only known ligand binding to a membrane receptor named receptor activator of nuclear factor-kappa B (RANK), thereby triggering recruitment of tumor necrosis factor (TNF) receptor associated factor (TRAF) adaptor proteins and activation of downstream pathways. RANK/RANKL signaling is controlled by a decoy receptor called osteoprotegerin (OPG), but also has additional more complex levels of regulation. The existing literature on RANK/RANKL signaling in cervical cancer was reviewed, particularly focusing on the effects on the microenvironment. RANKL and RANK are frequently co-expressed in cervical cancer cells lines and in carcinoma of the uterine cervix. RANKL and OPG expression strongly increases during cervical cancer progression. RANKL is directly secreted by cervical cancer cells, which may be a mechanism they use to create an immune suppressive environment. RANKL induces expression of multiple activating cytokines by dendritic cells. High RANK mRNA levels and high immunohistochemical OPG expression are significantly correlated with high clinical stage, tumor grade, presence of lymph node metastases, and poor overall survival. Inhibition of RANKL signaling has a direct effect on tumor cell proliferation and behavior, but also alters the microenvironment. Abundant circumstantial evidence suggests that RANKL inhibition may (partially) reverse an immunosuppressive status. The use of denosumab, a monoclonal antibody directed to RANKL, as an immunomodulatory strategy is an attractive concept which should be further explored in combination with immune therapy in patients with cervical cancer.

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Schmiedel, Benjamin J., Carolin Scheible, Tina Baessler, Constantin M. Wende, Stefan Wirths, Miyuki Azuma, Pascal Schneider, Ludger Grosse-Hovest, Lothar Kanz, and Helmut R. Salih. "Fc-Engineered RANK-Fc Fusion Proteins for Neutralization of Soluble RANKL and Induction of Antibody-Dependent Cellular Cytotoxicity (ADCC) Against Multiple Myeloma." Blood 116, no. 21 (November 19, 2010): 3039. http://dx.doi.org/10.1182/blood.v116.21.3039.3039.

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Abstract Abstract 3039 Bone resorption is commonly associated with aging, but also with certain cancers. Recent studies identified Receptor Activator of NF-κB (RANK) ligand (RANKL) and its receptors RANK and osteoprotegerin as key regulators of bone remodelling. Multiple myeloma (MM) disrupts the balance within this molecule system towards osteoclastogenesis and bone destruction. Neutralization of RANKL by the monoclonal antibody Denosumab (AMG162) is presently being evaluated for treatment of both non-malignant and malignant osteolysis. We found, in line with previously published data, that primary MM cells (9 of 10) express substantial levels of RANKL at the cell surface and that MM cells directly release RANKL in soluble form (sRANKL). Next we evaluated the possibility to combine neutralization of sRANKL with targeting of MM cells for antibody-dependent cellular cytotoxicity (ADCC) of NK cells utilizing RANK-Ig fusion proteins with modified Fc portions. Compared to wildtype RANK-Fc, our mutants (S239D/I332E and E233P/L234V/L235A/DG236/A327G/A330S) displayed highly enhanced (RANK-Fc-ADCC) and abrogated (RANK-Fc-KO) affinity, respectively, to the NK cell FcγRIIIa, but comparable capacity to neutralize RANKL in binding competition and osteoclast formation assays. Analyses with RANKL transfectants and RANKL-negative controls confirmed the high and lacking potential of the RANK-Fc-ADCC and the RANK-Fc-KO to induce NK ADCC, respectively, and ascertained that the RANK-Fc-ADCC specifically induced NK cell lysis of RANKL-expressing but not RANKL-negative target cells. Most notably, in cultures of NK cells with RANKL-expressing primary MM cells RANK-Fc-ADCC potently enhanced NK cell degranulation, cytokine release and MM cells lysis due to enhanced NK reactivity. Thus, our Fc-engineered RANK-Fc-ADCC fusion protein may both neutralize detrimental effects of sRANKL and enhance NK anti-tumor reactivity by targeting RANKL-expressing malignant cells thereby constituting an attractive immunotherapeutic means for treatment of MM. Disclosures: No relevant conflicts of interest to declare.

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Santos, Raí Matheus Carvalho, and Cristiane Batista Bezerra Torres. "Papel do sistema RANKL/RANK/OPG como regulador-chave da remodelação óssea durante a movimentação ortodôntica." Jornal Interdisciplinar de Biociências 2, no. 1 (May 12, 2017): 31. http://dx.doi.org/10.26694/2448-0002.vl2iss1pp31-34.

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RANKL, RANK e OPG têm sido apontados como reguladores da osteoclastogênese. O RANKL é produzido por células ósseas ou do ligamento periodontal em resposta a forças ortodônticas. Seu receptor de membrana RANK é encontrado em células precursoras de osteoclastos. Vários tipos de células produzem osteoprotegerina (OPG), uma citocina com afinidade ao RANKL e efeito inibitório sobre ele. O objetivo do presente trabalho foi buscar evidências científicas, por meio de pesquisa bibliográfica, do papel do sistema RANKL/RANK/OPG na remodelação óssea durante a movimentação dentária ortodôntica. Artigos foram recuperados nas bases de dados bibliográficos LILACS, MEDLINE, PubMed e SciELO, por meio dos termos de busca “rankl” e “orthodontic tooth movement”. Resultados de pesquisas sugerem que RANKL ativa a osteoclastogênese, com consequente aceleração do movimento do dente, enquanto a OPG o reduz, pela inibição da ligação RANKL/RANK. O controle de RANKL/RANK, em nível de receptores ou via de sinalização, pode ser uma ferramenta efetiva no tratamento de reabsorção óssea indesejada, abrindo campo promissor para novas abordagens farmacológicas no tratamento ortodôntico e remodelação óssea alveolar. https://doi.galoa.com.br/doi/10.17648/jibi-2448-0002-2-1-5443

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Chen, Xiao-Wen, Xiao-Yan Du, Yu-Xian Wang, Jian-Cheng Wang, Wen-Ting Liu, Wen-Jing Chen, Hong-Yu Li, et al. "Irbesartan Ameliorates Diabetic Nephropathy by Suppressing the RANKL-RANK-NF-κB Pathway in Type 2 Diabetic db/db Mice." Mediators of Inflammation 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/1405924.

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The receptor activator of NF-κB ligand (RANKL) and its receptor RANK are overexpressed in focal segmental glomerular sclerosis (FSGS), IgA nephropathy (IgAN), and membranous nephropathy (MN). However, the expression and the potential roles of RANKL and RANK in diabetic nephropathy (DN) remain unclear. Irbesartan (Irb) has beneficial effects against diabetes-induced renal damage, but its mechanisms are poorly understood. Our present study investigated the effects of Irb in DN and whether the renal protective effects of Irb are mediated by RANKL/RANK and the downstream NF-κB pathway in db/db mice. Our results showed that db/db mice revealed severe metabolic abnormalities, renal dysfunction, podocyte injury, and increased MCP-1; these symptoms were reversed by Irb. At the molecular level, RANKL and RANK were overexpressed in the kidneys of db/db mice and Irb downregulated RANKL and RANK and inhibited the downstream NF-κB pathway. Our study suggests that Irb can ameliorate DN by suppressing the RANKL-RANK-NF-κB pathway.

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Sigl, Verena, Laundette P. Jones, and Josef M. Penninger. "RANKL/RANK: from bone loss to the prevention of breast cancer." Open Biology 6, no. 11 (November 2016): 160230. http://dx.doi.org/10.1098/rsob.160230.

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RANK and RANKL, a receptor ligand pair belonging to the tumour necrosis factor family, are the critical regulators of osteoclast development and bone metabolism. Besides their essential function in bone, RANK and RANKL have also been identified as the key factors for the formation of a lactating mammary gland in pregnancy. Mechanistically, RANK and RANKL link the sex hormone progesterone with stem cell expansion and proliferation of mammary epithelial cells. Based on their normal physiology, RANKL/RANK control the onset of hormone-induced breast cancer through the expansion of mammary progenitor cells. Recently, we and others were able to show that RANK and RANKL are also critical regulators of BRCA1 -mutation-driven breast cancer. Currently, the preventive strategy for BRCA1 -mutation carriers includes preventive mastectomy, associated with wide-ranging risks and psychosocial effects. The search for an alternative non-invasive prevention strategy is therefore of paramount importance. As our work strongly implicates RANK and RANKL as key molecules involved in the initiation of BRCA1-associated breast cancer, we propose that anti-RANKL therapy could be a feasible preventive strategy for women carrying BRCA1 mutations, and by extension to other women with high risk of breast cancer.

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Krejsek, Jan, Martina Koláčková, Vladimír Lonský, Manuela Trojáčková Kudlová, Jiří Manďák, Pavel Kuneš, Karolína Jankovičová, Dana Vlášková, and Ctirad Andrýs. "RANK/RANKL Expression Is Induced by Cardiac Surgical Operation." Acta Medica (Hradec Kralove, Czech Republic) 52, no. 4 (2009): 149–53. http://dx.doi.org/10.14712/18059694.2016.121.

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Background: Cardiac surgery provokes a systemic inflammatory response in any patient. This complex body reaction involves also RANK/RANKL molecules which have been recently identified as principal regulators of bone metabolism. Aims: To follow the changes in the expression of RANK/RANKL molecules on innate immune cells of cardiac surgical patients. Patients and Methods: Twenty-six patients undergoing cardiac surgical were assigned to undergo coronary artery bypass grafting using either cardiopulmonary bypass (“on-pump”) or modified “miniinvasive on-pump”. The expression of RANK/RANKL was performed by flow cytometry. Results: Significantly increased expression of RANK on monocytes of “miniinvasive on-pump” patients was found at the 1st, the 3nd, and 7th postoperative days. The similar pattern was found also for monocyte RANKL expression. In addition, RANKL expression was significantly increased at the 3rd postoperative day in “on-pump” patient. No significant differences between “miniinvasive on-pump” and “on-pump” cardiac surgical patients were found. Conclusion: The expression of both RANK and RANKL molecules is significantly enhanced on monocytes of “miniinvasive on-pump” cardiac surgical patients.

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Wieser, Verena, Susanne Sprung, Irina Tsibulak, Johannes Haybaeck, Hubert Hackl, Heidelinde Fiegl, Christian Marth, and Alain Gustave Zeimet. "Clinical Impact of RANK Signalling in Ovarian Cancer." Cancers 11, no. 6 (June 8, 2019): 791. http://dx.doi.org/10.3390/cancers11060791.

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Ovarian cancer (OC) is a gynaecological malignancy with poor clinical outcome and limited treatment options. The receptor activator of nuclear factor-κB (RANK) pathway, activated by RANK ligand (RANKL), critically controls bone metabolism, tumourigenesis and tumour immune responses. Denosumab, a monocloncal RANKL antibody, exerts tumour-suppressive effects in mice and humans. Here, we investigated the relevance of RANK signalling in OC. RANK, RANKL and OPG expression in 192 epithelial OC tissues was compared to expression in 35 non-malignant control tissues and related to clinico-pathological characteristics. Findings were validated in a cohort of 563 OC patients from The Cancer Genome Atlas (TCGA). The expression of RANK, RANKL and OPG was studied in four OC cell lines and the impact of RANK ligation or blockade on OC cell proliferation was determined. RANK, RANKL and OPG were expressed in epithelial and stromal cells in OC. RANKL expression was elevated in OC tissue, particularly in BRCA1/2 mutated tumours. High RANKL expression independently predicted reduced progression-free (PFS, p = 0.017) and overall survival (OS, p = 0.007), which could be validated in the TCGA cohort (PFS, p = 0.022; OS, p = 0.046, respectively). Expression of RANK and OPG in OC cells was induced by inflammatory cytokines IL-1β and TNFα. Neither recombinant RANK ligation nor denosumab treatment affected OC cell proliferation. Our study independently links RANKL expression with poor clinical outcome in two unrelated OC cohorts. These findings implicate RANK signalling in the immunopathogenesis of OC and warrant clinical trials with denosumab in OC.

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Li, Xuefei, Longkang Cui, Wenhua Chen, Yuan Fang, Gaobo Shen, Zhen Li, Bingbing Zhang, and Lianguo Wu. "QiangGuYin Modulates the OPG/RANKL/RANK Pathway by Increasing Secretin Levels during Treatment of Primary Type I Osteoporosis." Evidence-Based Complementary and Alternative Medicine 2021 (October 31, 2021): 1–11. http://dx.doi.org/10.1155/2021/7114139.

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QiangGuYin (QGY) is a common Traditional Chinese medicine prescription for the treatment of osteoporosis. Previous clinical studies have found that QGY effectively improves bone mineral density (BMD) in postmenopausal women, but its underlying mechanism remains unclear. The osteoprotegerin (OPG)/receptor activator of nuclear factor kappa B ligand (RANKL)/receptor activator of nuclear factor kappa B (RANK) pathway is a classic pathway involved in osteoporosis. Secretin levels are a serum marker of osteoporosis, but their effect on the OPG/RANKL/RANK pathway has not been reported. Hence, we investigated the relationship between the OPG/RANKL/RANK pathway and secretin and further revealed the mechanism underlying the effect of QGY in the treatment of osteoporosis. Mice were divided into secretin knockdown, secretin overexpression, and corresponding control groups. Micro-computed tomography was used to detect BMD in different groups, and the results show that QGY significantly improved BMD in mice of the secretin knockdown group. To further verify this, the serum levels of OPG, RANKL, RANK, and secretin were measured by enzyme-linked immunosorbent assays, and femur levels of OPG, RANKL, RANK, and secretin were evaluated by real-time quantitative PCR and western blotting. The results show that the expression of OPG was inhibited and that of RANKL and RANK was increased in mice from the secretin knockdown group, whereas the expression of OPG was upregulated and that of RANKL and RANK was downregulated after QGY intervention. Therefore, QGY inhibited bone resorption by promoting the expression of secretin and modulating the OPG/RANKL/RANK pathway. In addition to the effect of QGY, we also revealed the general regulatory effect of secretin on the OPG/RANKL/RANK pathway. We conclude that QGY modulates the OPG/RANKL/RANK pathway by increasing secretin levels during treatment of primary type I osteoporosis. This work provides a theoretical basis for the clinical use of QGY in the treatment of osteoporosis.

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Schmiedel, Benjamin J., Constantin M. Wende, Tina Baessler, Carolin Scheible, Stefan Wirths, Miyuki Azuma, Pascal Schneider, Ludger Grosse-Hovest, Lothar Kanz, and Helmut R. Salih. "RANKL Expressed by Acute Myeloid Leukemia Cells Impairs NK Cell-Mediated Immune Surveillance." Blood 116, no. 21 (November 19, 2010): 2164. http://dx.doi.org/10.1182/blood.v116.21.2164.2164.

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Abstract Abstract 2164 NK cells play an important role in tumor immunosurveillance, especially of leukemia. Their reactivity is governed by various activating and inhibitory molecules expressed by their targets including multiple members of the TNF family. The TNF family member Receptor Activator of NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin (OPG) are key regulators of bone remodelling, but recently have also been shown to influence progression of hematopoetic malignancies. Here we studied the yet unkown role of the RANK/RANKL molecule system in NK cells and their reactivity against acute myeloid leukemia (AML). Primary leukemia cells from AML patients were found to substantially express RANKL mRNA and surface protein in 75% of the investigated cases (n=40). Reverse signaling via surface-expressed RANKL into AML blasts induced the release of soluble factors including the immunoregulatory cytokines TNF and IL-10, which impaired NK cell anti-tumor reactivity. Moreover, we observed upregulation of RANK on NK cells among PBMC of healthy donors upon exposure to IL-10. This was not caused by direct effects on NK cells, but was rather due to yet unidentified factors released by monocytes among the PBMC upon IL-10 exposure and could be prevented by the activating cytokine IL-2. Furthermore, functional experiments with NK cells and RANKL transfectants or RANKL-negative controls revealed that forward signaling into RANK-expressing NK cells by tumor-expressed RANKL also directly impaired NK cytotoxicity and IFN-γ production. In line, blocking RANK-RANKL interaction using anti-RANKL antibodies or RANK-Fc fusion protein increased cytotoxicity and cytokine production of allogenic NK cells in cultures with RANKL-positive primary AML cells. Our data indicate that RANKL expression enables immune evasion of leukemia cells both by directly inhibiting reactivity of RANK-expressing NK cells and by orchestrating a reciprocal interplay between AML cells, monocytes and NK cells resulting in an immunosuppressive cytokine milieu. Thus, therapeutic modulation of the RANK/RANKL system, e.g. with Denosumab/AMG162, which is presently being evaluated for treatment of both non-malignant and malignant osteolysis, holds promise to reinforce NK reactivity against hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

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Schmiedel, Benjamin J., Tina Baessler, Miyuki Azuma, Lothar Kanz, and Helmut R. Salih. "Expression and Immunomodulatory Function of RANKL in Leukemia." Blood 118, no. 21 (November 18, 2011): 245. http://dx.doi.org/10.1182/blood.v118.21.245.245.

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Abstract Abstract 245 The TNF family member RANKL and its receptors RANK and osteoprotegerin (OPG) are key regulators of bone remodelling, but have also been shown to influence progression of malignancies like breast cancer (Tan et al., Nature 2011), myeloma (Sordillo et al., Cancer 2003) and CLL (Secchiero et al. J Cell Physiol. 2006). NK cells are cytotoxic lymphocytes that play an important role in tumor immune surveillance especially of hematopoietic malignancies. Their reactivity is influenced by a variety of activating and inhibitory molecules expressed by their target cells including several members of the TNF family. Recently, we reported that RANK, upon interaction with RANKL which can be expressed by malignant hematopoietic cells, mediates signals that impair NK reactivity (Schmiedel et al., Blood 2010 116,21:893–893). Here we extended these analyses and comprehensively studied the expression and immunomodulatory function of RANKL in leukemia. Analysis of primary leukemia cells revealed substantial RANKL surface expression in a high proportion of the investigated cases (AML, 47 of 65 (72%); ALL, 16 of 21 (76%); CML, 6 of 10 (60%); CLL, all 54 (100%)). Signaling via surface-expressed RANKL into the malignant cells mediated the release of cytokines like TNF, IL-6, IL-8 and IL-10 which have been shown to act as autocrine and paracrine growth and survival factors in leukemia. Moreover, the factors released upon RANKL signaling upregulated RANK expression on NK cells. In line, NK cells from leukemia patients (n=75) displayed significantly (p<0.001, Mann-Whitney U-test) higher RANK expression compared to healthy controls (n=30) confirming our notion that RANK-RANKL interaction may contribute to leukemia pathophysiology. We further found that RANK-RANKL interaction, beyond directly inhibiting NK cell function via RANK, may contribute to evasion of leukemia cells from NK immunosurveillance by creating an NK inhibitory cytokine milieu. This was revealed by impaired cytotoxicity and degranulation in response to leukemia targets following exposure of the NK cells to the factors released upon RANKL signaling by leukemia cells. Notably, the RANKL-mediated cytokine release of leukemia cells could be disrupted by the clinically approved RANKL antibody Denosumab/AMG162. Thus, RANKL signaling may trigger a “vicious cycle” comprising of release of immunosuppressive cytokines and also upregulation of RANK on NK cells. The latter both directly inhibits NK reactivity and may result in augmented RANKL signaling into leukemia cells. Our data suggest that therapeutic modulation of the RANK/RANKL system e.g. with Denosumab/AMG162, which is approved for treatment of osteolysis, may be a promising strategy to reinforce NK reactivity against hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

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He, Xianfeng, Limei Zhu, Lin An, and Jingwei Zhang. "MiR-143 Inhibits Osteoclastogenesis by Targeting RANK and NF-κB and MAPK Signaling Pathways." Current Molecular Pharmacology 13, no. 3 (July 9, 2020): 224–32. http://dx.doi.org/10.2174/1874467213666200116113945.

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Objective: To explore the effect of miRNA-143 on osteoclast formation and provide new ideas for the treatment of osteoporosis. Methods: Mice macrophage lines RAW264.7 cells after transfection were divided into four groups: control group, RANKL group, RANKL combined with miR-143 mimics group and RANKL combined with miR-NC group. TARCP staining was used to observe the effect of miR-143 on osteoclast formation. The expression of RANK, TRAF6 and NFATc-1 in the upstream of RANKL pathway was detected by real-time quantitative PCR (RT qPCR) and Western blotting (WB). The binding of miR-143 to TNFRSF11A was detected by double Luciferase Reporter Analysis. The effect of miR-143 on the expression of NF-κB (p65, I-κB-α) signal pathway in osteoclasts was detected. The effects of I-BET151 on the expression of osteoclast-specific genes TRACP, MMP 9, CtsK and c-Src were detected. Results: The positive level of osteoclasts in RANKL group and RANKL combined with miR-NC group was significantly higher than that of RANKL combined with miR-143 mimics group and control group (P < 0.05). The expression levels of RANK, TRAF6, NFATc-1, TRACP, MMP-9, CtsK and c-Src in RANKL group and RANKL combined with miR-NC group were significantly higher than those of RANKL combined with miR-143 mimics group and control group (P < 0.05). The expression levels of I-κB-α were significantly lower than that of RANKL combined with miR-143 mimics group and control group (P<0.05). Conclusion: MiR-143 can inhibit the expression of RANK, TRAF6 and downstream NFATc-1 in the RANKL pathway, thereby inhibiting the RANK/RANKL pathway. MiR-143 can inhibit the signal pathway of NF-κB (p65, I-κB-α). MiR-143 inhibits the expression of osteoclast-specific genes TRACP, MMP 9, CtsK and c-Src. That is to say, miR-143 inhibits osteoclast formation by targeting RANK, NF- κB and MAPK signaling pathways.

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Simatou, Aristofania, Panagiotis Sarantis, Evangelos Koustas, Athanasios G. Papavassiliou, and Michalis V. Karamouzis. "The Role of the RANKL/RANK Axis in the Prevention and Treatment of Breast Cancer with Immune Checkpoint Inhibitors and Anti-RANKL." International Journal of Molecular Sciences 21, no. 20 (October 14, 2020): 7570. http://dx.doi.org/10.3390/ijms21207570.

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The receptor activator of nuclear factor-κB (RANK) and the RANK ligand (RANKL) were reported in the regulation of osteoclast differentiation/activation and bone homeostasis. Additionally, the RANKL/RANK axis is a significant mediator of progesterone-driven mammary epithelial cell proliferation, potentially contributing to breast cancer initiation and progression. Moreover, several studies supported the synergistic effect of RANK and epidermal growth factor receptor (EGFR) and described RANK’s involvement in epidermal growth factor receptor 2 (ERBB2)-positive carcinogenesis. Consequently, anti-RANKL treatment has been proposed as a new approach to preventing and treating breast cancer and metastases. Recently, RANKL/RANK signaling pathway inhibition has been shown to modulate the immune environment and enhance the efficacy of anti-CTLA-4 and anti-PD-1 monoclonal antibodies against solid tumors. Clinical and experimental trials have emerged evaluating RANKL inhibition as an enhancer of the immune response, rendering resistant tumors responsive to immune therapies. Trials evaluating the combinatorial effect of immune checkpoint inhibitors and anti-RANKL treatment in double-positive (RANK+/ERBB2+) patients are encouraging.

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Akiyama, Taishin. "RANKL-RANK interaction in immune regulatory systems." World Journal of Orthopedics 3, no. 9 (2012): 142. http://dx.doi.org/10.5312/wjo.v3.i9.142.

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Bhuvaneswarri, J., V. Ramya, Preethe Padmanabhan, Sajid T. Hussain, and U. Vidhya Rekha. "Rank/Rankl Factor in Periodontitis―A Review." Indian Journal of Public Health Research & Development 10, no. 12 (December 1, 2019): 2338. http://dx.doi.org/10.37506/v10/i12/2019/ijphrd/192362.

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Yamaguchi, M. "RANK/RANKL/OPG during orthodontic tooth movement." Orthodontics & Craniofacial Research 12, no. 2 (May 2009): 113–19. http://dx.doi.org/10.1111/j.1601-6343.2009.01444.x.

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Pérez-Sayáns, Mario, José Manuel Somoza-Martín, Francisco Barros-Angueira, José Manuel Gándara Rey, and Abel García-García. "RANK/RANKL/OPG role in distraction osteogenesis." Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 109, no. 5 (May 2010): 679–86. http://dx.doi.org/10.1016/j.tripleo.2009.10.042.

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Oralova, Veronika, Sabina Stouracova, Mary Clarke, Jon Frampton, Petr Benes, and Eva Matalova. "Myb deficiency impacts Rank-Rankl-Opg system." Bone Reports 13 (October 2020): 100406. http://dx.doi.org/10.1016/j.bonr.2020.100406.

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Xi, Lei, Hailong Cao, and Yijiang Chen. "OPG/RANK/RANKL Axis in Atrial Fibrillation." Cardiology 125, no. 3 (2013): 174–75. http://dx.doi.org/10.1159/000351441.

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Li, Jiali, Christina Yau, Michael Campbell, Laura Esserman, John W. Park, and Hope S. Rugo. "Correlation of receptor activator of nuclear factor kappa b (RANK) expression in breast cancer (BC) at the time of diagnosis with recurrence-free survival (RFS) and risk of bone-dominant metastases (BDM) in the I-SPY 1 trial (CALGB 150007/150012; ACRIN 6657)." Journal of Clinical Oncology 30, no. 27_suppl (September 20, 2012): 2. http://dx.doi.org/10.1200/jco.2012.30.27_suppl.2.

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2 Background: RANK is a tumor necrosis factor receptor family protein that is critical to bone turnover. The ligand to RANK (RANKL) can induce metastases from RANK-expressing tumor cells, and treatment with a RANKL inhibitor can reduce BC metastases (mets) in pre-clinical models and there is an FDA approved drug that targets RANKL. Osteoprotegerin (OPG) is a RANKL decoy receptor that blocks the interaction of RANK/RANKL. I-SPY 1 was a multicenter neoadjuvant trial with well annotated gene expression data and detailed clinical outcomes; we studied the impact of RANK expression on both RFS and BDM. Methods: OPG/RANK/RANKL pathway expression in core biopsies was evaluated at diagnosis in patients (pts) on I-SPY 1, then correlated with ER, intrinsic subtype, stage, response to chemotherapy, site of mets and RFS using the student t-test. Results: Gene arrays were performed on pretreatment tumor from 221 pts; 149 pts have available data with n being ER+. At a median follow-up of 3.5 yrs, 36 pts developed recurrence; 13 pts had BDM, 15 had non-bone mets (NBDM), and 8 pts were not evaluable. RANK, but not OPG or RANKL, was more highly expressed in ER- vs ER+ tumors (p=0.04) and in basal vs luminal A/B subtypes (p= 0.04), but no difference in expression based on tumor grade, node status or response to chemotherapy. Higher (>50%) RANK and lower (<50%) OPG expression correlated with worse RFS (p=0.03). Pts who developed BDM had higher expression of RANK, but not RANKL or OPG compared those with NBDM (p=0.05). After adjusting for ER and intrinsic subtypes, RANK expression was even more significantly correlated with risk for BDM (p=0.004). Conclusions: Higher RANK and lower OPG expression in primary tumor tissue correlates with poor RFS, and high RANK expression is associated with increased risk for BDM. These data suggests that targeting the OPG/RANK/RANKL pathway could be a promising strategy in preventing BDM in pts with high risk BC.

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Arai, Fumio, Takeshi Miyamoto, Osamu Ohneda, Tomohisa Inada, Tetsuo Sudo, Kenneth Brasel, Takashi Miyata, Dirk M. Anderson, and Toshio Suda. "Commitment and Differentiation of Osteoclast Precursor Cells by the Sequential Expression of C-Fms and Receptor Activator of Nuclear Factor κb (Rank) Receptors." Journal of Experimental Medicine 190, no. 12 (December 20, 1999): 1741–54. http://dx.doi.org/10.1084/jem.190.12.1741.

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Osteoclasts are terminally differentiated cells derived from hematopoietic stem cells. However, how their precursor cells diverge from macrophagic lineages is not known. We have identified early and late stages of osteoclastogenesis, in which precursor cells sequentially express c-Fms followed by receptor activator of nuclear factor κB (RANK), and have demonstrated that RANK expression in early-stage of precursor cells (c-Fms+RANK−) was stimulated by macrophage colony-stimulating factor (M-CSF). Although M-CSF and RANKL (ligand) induced commitment of late-stage precursor cells (c-Fms+RANK+) into osteoclasts, even late-stage precursors have the potential to differentiate into macrophages without RANKL. Pretreatment of precursors with M-CSF and delayed addition of RANKL showed that timing of RANK expression and subsequent binding of RANKL are critical for osteoclastogenesis. Thus, the RANK–RANKL system determines the osteoclast differentiation of bipotential precursors in the default pathway of macrophagic differentiation.

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Hendrijantini, Nike, Rostiny Rostiny, Abil Kurdi, Muhammad D. A. Ari, Ratri M. Sitalaksmi, Primarinda D. Hapsari, Valentina V. Arief, and Puthi Y. I. Sati. "Molecular Triad RANK/ RANKL/ OPG in Mandible and Femur of Wistar Rats (Rattus norvegicus) With Type 2 Diabetes Mellitus." Recent Advances in Biology and Medicine 5 (2019): 1. http://dx.doi.org/10.18639/rabm.2019.959614.

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A successful treatment of dental implant needs a good jaw bone support, which depends on healthy bone metabolism. Bone metabolism can be affected by Diabetes Mellitus (DM). It may trigger various complications, including osteoporosis. Molecular triads consisting of Receptor Activator of NF-kappaB (RANK), Activator of nF-κB Ligand (RANKL), and osteoprotegerin (OPG), have an important role in the formation, function, and osteoclast survival. In this study, molecular triads were observed on mandible and femur bones in type 2 DM Wistar rats. The aim of this study was to observe the molecular triad RANK / RANKL / OPG expressions in type 2 DM Wistar rats. This laboratory research used 18 male Wistar rats divided into three groups: nondiabetic group (control), uncontrolled DM injected with single dose of Streptozotocin (STZ), and controlled DM treated with Metformin. On day 20, the mandible and femur were collected and specimen processing was carried out. The results of RANK / RANKL / OPG expressions were obtained from immunohistochemical staining. In both mandible and femur groups, RANK, RANKL, OPG expressions showed no difference between the control and uncontrolled DM groups. RANKL / OPG ratio in uncontrolled DM was higher than that in the control group. RANK expression was lower in uncontrolled DM group compared with controlled DM, and the RANKL expression in uncontrolled DM group was higher than that in the controlled DM group. RANKL / OPG ratio was lower in the controlled DM group. The study suggested that DM affects resorptive activity in mandible and femur bones which can be observed via RANK/RANKL/OPG.

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Wu, Ruixian, Qian Li, Xiaohua Pei, and Kefei Hu. "Effects of Brucine on the OPG/RANKL/RANK Signaling Pathway in MDA-MB-231 and MC3T3-E1 Cell Coculture System." Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–6. http://dx.doi.org/10.1155/2017/1693643.

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The present study examined the effects of brucine on the OPG/RANKL/RANK signaling pathway for exploring the mechanism of brucine suppression of bone metastasis in breast cancer. MDA-MB-231 breast cancer cells and mouse osteoblast MC3T3-E1 cells were cocultured to mimic the breast cancer bone metastasis microenvironmentin vitro. qRT-PCR and Western blotting were used to detect the expressions of OPG and RANKL at the mRNA and protein levels, respectively, in brucine-treated cultures and they were compared to those in untreated cultures. We aimed to understand the effect of brucine on the entire OPG/RANKL/RANK signaling pathway after analyzing these effects. Results showed that brucine treatment significantly increased both the OPG mRNA/RANKL mRNA expression ratio and the OPG protein/RANKL protein ratio in cocultures compared to those in untreated cocultures (P<0.01). Brucine, therefore, plays a regulatory role in the OPG/RANKL/RANK signaling pathway, suggesting that it can indirectly control osteoclasts by regulating the expression and secretion of OPG and RANKL in osteoblast cells, thereby inhibiting the differentiation and bone resorption function of osteoclasts.

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Jimi, Eijiro. "Modulation of Osteoclast Differentiation by RANKL-RANK Signaling." Journal of the Kyushu Dental Society 59, no. 5.6 (2005): 199–209. http://dx.doi.org/10.2504/kds.59.199.

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Mota, Ryerson Fonseca, Paulo Henrique Cavalcanti de Araújo, Maria Eduarda Ramos Cezine, Flávia Sayuri Matsuo, Rodrigo Jair Morandi Metzner, Carlos Alberto Oliveira de Biagi Junior, Kamila Chagas Peronni, et al. "RANKL Impairs the TLR4 Pathway by Increasing TRAF6 and RANK Interaction in Macrophages." BioMed Research International 2022 (April 12, 2022): 1–13. http://dx.doi.org/10.1155/2022/7740079.

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High serum levels of osteoprotegerin (OPG) are found in patients with obesity, type 2 diabetes, sepsis, or septic shock and are associated with a high mortality rate in stroke. The primary known function of OPG is to bind to the receptor activator of NF-κB ligand (RANKL), and by doing so, it inhibits the binding between RANKL and its receptor (RANK). TLR4 signaling in macrophages involves TRAF6 recruitment and contributes to low-grade chronic inflammation in adipose tissue. LPS is a classical activator of the TLR4 pathway and induces the expression of inflammatory cytokines in macrophages. We have previously observed that in the presence of RANKL, there is no LPS-induced activation of TLR4 in macrophages. In this study, we investigated the crosstalk between RANK and TLR4 pathways in macrophages stimulated with both RANKL and LPS to unveil the role of OPG in inflammatory processes. We found that RANKL inhibits TLR4 activation by binding to RANK, promoting the binding between TRAF6 and RANK, lowering TLR4 activation and the expression of proinflammatory mediators. Furthermore, high OPG levels aggravate inflammation by inhibiting RANKL. Our findings elect RANKL as a candidate for drug development as a way to mitigate the impact of obesity-induced inflammation in patients.

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Wang, Chin-Man, Shu-Chun Tsai, Jing-Chi Lin, Yeong-Jian Jan Wu, Jianming Wu, and Ji-Yih Chen. "Association of Genetic Variants of RANK, RANKL, and OPG with Ankylosing Spondylitis Clinical Features in Taiwanese." Mediators of Inflammation 2019 (March 20, 2019): 1–14. http://dx.doi.org/10.1155/2019/8029863.

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Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.

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Gutierrez, Humberto, Lilian Kisiswa, Gerard W. O'Keeffe, Matthew J. Smithen, Sean Wyatt, and Alun M. Davies. "Regulation of neurite growth by tumour necrosis superfamily member RANKL." Open Biology 3, no. 1 (January 2013): 120150. http://dx.doi.org/10.1098/rsob.120150.

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RANKL (receptor-activator of NF-κB ligand, TNFSF11) is a member of the TNF superfamily that regulates bone remodelling and the development of the thymus, lymph nodes and mammary glands. While RANKL and its membrane bound receptor RANK (TNFRSF11A) are expressed in the adult central nervous system and have been implicated in thermoregulation, the potential function of RANK signalling in the developing nervous system remains unexplored. Here, we show that RANK is expressed by sympathetic and sensory neurons of the developing mouse peripheral nervous system and that activating RANK signalling in these neurons during perinatal development by either treating cultured neurons with soluble RANKL or overexpressing RANK in the neurons inhibited neurotrophin-promoted neurite growth without affecting neurotrophin-promoted neuronal survival. RANKL is expressed in tissues innervated by these neurons, and studies in compartment cultures demonstrated that RANKL is capable of acting directly on neurites to inhibit growth locally. Enhancing RANK signalling in cultured neurons resulted in NF-κB activation and phosphorylation of the p65 NF-κB subunit on serine 536. Transfecting neurons with a series of mutated signalling proteins showed that NF-κB activation and p65 phosphorylation occurred by an IKKβ-dependent mechanism and that blockade of this signalling pathway prevented neurite growth inhibition by RANKL. These findings reveal that RANKL is a novel negative regulator of neurite growth from developing PNS neurons and that it exerts its effects by IKKβ-dependent activation of NF-κB.

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Al-Rawi, Natheer H., Ammar K. Al-Siraj, and Ahlam H. Majeed. "Comparison of osteoclastogenesis and local invasiveness of ameloblastoma and keratocystic odontogenic tumor." European Journal of Dentistry 12, no. 01 (January 2018): 036–42. http://dx.doi.org/10.4103/ejd.ejd_54_17.

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Abstract: Objectives The aim of this study was to compare the expression of receptor-activated nuclear factor kappa B (RANK) with its ligand (RANKL) and matrix metalloproteinase-2 (MMP2) in solid/multicystic ameloblastomas (ABs) and keratocystic odontogenic tumors (KOTs). Materials and Methods: The expression of MMP2, RANK, and RANKL molecules was evaluated in 13 ABs and 14 KOTs by immunohistochemistry. The expressions were calculated in the odontogenic epithelial cells as well as the stromal cells. Results: Odontogenic epithelia of AB expressed MMP2, RANK, and RANKL significantly higher than that of KOTs (P < 0.05). The expression of MMP2, RANK, and RANKL was highest in plexiform subtype (79.9%, 81.08%, and 65.1%, respectively). KOTs without daughter epithelia nests expressed both MMP2 and RANK the least (56.06% and 47.5%, respectively). Stromal cells, on the other hand, expressed similar MMP2 pattern in odontogenic epithelia of both AB and KOT. RANKL was expressed weaker in the stromal cells of both lesions. Conclusion: Invasive biological and osteolytic behaviors of both lesions were evaluated in this study. It was found to be more in AB than keratocystic odontogenic. A significant expression of MMP2, RANK, and RANKL in both KOTs associated with microcyst and plexiform type AB as well.

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MELCHIORRE, DANIELA, ANNA FRANCA MILIA, SILVIA LINARI, ELOISA ROMANO, GEMMA BENELLI, MIRKO MANETTI, SERENA GUIDUCCI, et al. "RANK-RANKL-OPG in Hemophilic Arthropathy: From Clinical and Imaging Diagnosis to Histopathology." Journal of Rheumatology 39, no. 8 (July 1, 2012): 1678–86. http://dx.doi.org/10.3899/jrheum.120370.

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Objective.Hemarthrosis triggers hemophilic arthropathy, involving the target joints. The histopathogenesis of blood-induced joint damage remains unclear. The triad of receptor activator of nuclear factor-κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG; RANK-RANKL-OPG) controls bone turnover. Our aim was to evaluate RANK-RANKL-OPG expression in the synovium of hemophilic patients with severe arthropathy.Methods.Synovial biopsies were obtained from 18 patients with hemophilic arthropathy and 16 with osteoarthritis (OA) who were undergoing total knee replacement and synovectomy. The severity of hemophilic arthropathy was evaluated according to ultrasonography score, the World Federation of Hemophilia (WFH) orthopedic joint scale, and the radiographic Pettersson score. RANK-RANKL-OPG expression was examined by immunohistochemistry and Western blotting. Serum levels of soluble RANKL (sRANKL) and OPG from an extended group of 67 patients with hemophilic arthropathy and 30 healthy controls were measured by ELISA.Results.The mean ultrasonography, WFH orthopedic joint scale, and Pettersson scores in patients with hemophilic arthropathy indicated severe arthropathy. A decreased expression of OPG was found in hemophilic arthropathy synovium compared with patients with OA. RANK and RANKL immunopositivity was strong in the lining and sublining layers in hemophilic arthropathy synovial tissue. Western blotting confirmed the immunohistological findings. Serum levels of sRANKL and OPG in patients with hemophilia were lower than in healthy controls.Conclusion.In hemophilic arthropathy, the synovium highly expressed RANK and RANKL, whereas OPG immunopositivity decreased, suggesting an osteoclastic activation. Low tissue expression of OPG paralleled the serum levels of this protein and the severity of hemophilic arthropathy assessed by ultrasonography, Pettersson, and WFH orthopedic joint scale scores.

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Czupkallo, Lukasz, Mansur Rahnama, Dominik Kielbowicz, Michal Lobacz, and Maryla Kozicka-Czupkallo. "Bone metabolism and RANKL/RANK/OPG trail in periodontal disease." Current Issues in Pharmacy and Medical Sciences 29, no. 4 (December 1, 2016): 171–75. http://dx.doi.org/10.1515/cipms-2016-0036.

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Abstract Periodontal disease is an inflammatory disease of multifactorial etiology. In order for it to appear there must come to an imbalance between the effects of pathogens and host defense mechanisms. As a result of its course the destruction of structures supporting the teeth appears (periodontium, cement, bone), and consequently leads to teeth loosening and loss. In recent years, the participation of RANKL/RANK/OPG in bone remodeling process was highligted. At the molecular level the bone resorption is regulated through the interaction of the ligand receptor activator of nuclear NF-kappa B (RANKL) and osteoprotegerin (OPG), which is a system of two proteins belonging to the protein tumor necrosis factor (TNF). Recent findings about the RANKL protein and OPG have shed new light on the previously unexplained phenomenon of the basis of bone resorption. Research has shown that both protein OPG and RANKL can be detected in gingival crevicular fluid, which has become a window of opportunity in the analysis of non-invasive markers of periodontal tissues, confirming elevated levels of RANKL protein in periodontal disease, and decreased levels of OPG protein. Bone resorption is initiated by the binding of the RANKL protein to receptors RANK present on the surface of mature osteoclasts, and their precursors, which leads to the differentiation and activation of osteoclasts. OPG, being RANKL’s inhibitor, has, in turn, opposite characteristics to RANKL, resulting in the reduction of osteoclastogenesis process. Despite all this, the exact mechanism of bone resorption has not yet been elucidated.

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Melagraki, Georgia, Georgios Leonis, Evangelos Ntougkos, Vagelis Rinotas, Christos Papaneophytou, Thomas Mavromoustakos, George Kontopidis, Eleni Douni, George Kollias, and Antreas Afantitis. "Current Status and Future Prospects of Small–molecule Protein–protein Interaction (PPI) Inhibitors of Tumor Necrosis Factor (TNF) and Receptor Activator of NF-κB Ligand (RANKL)." Current Topics in Medicinal Chemistry 18, no. 8 (July 18, 2018): 661–73. http://dx.doi.org/10.2174/1568026618666180607084430.

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The overexpression of Tumor Necrosis Factor (TNF) is directly related to the development of several autoimmune diseases, such as rheumatoid and psoriatic arthritis, inflammatory bowel disease, Crohn's disease, refractory asthma, and multiple sclerosis. Receptor Activator of Nuclear Factor Kappa- B Ligand (RANKL) belongs to the TNF family and is the primary mediator of osteoclast-induced bone resorption through interaction with its receptor RANK. The function of RANKL is physiologically inhibited by the action of osteoprotegerin (OPG), which is a decoy receptor that binds to RANKL and prevents the process of osteoclastogenesis. Malfunction among RANK/RANKL/OPG can also result in bone loss diseases, including postmenopausal osteoporosis, rheumatoid arthritis, bone metastasis and multiple myeloma. To disrupt the unwanted functions of TNF and RANKL, current attempts focus on blocking TNF and RANKL binding to their receptors. In this review, we present the research efforts toward the development of low-molecular-weight pharmaceuticals that directly block the detrimental actions of TNF and RANKL.

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Schmiedel, Benjamin J., Tina Baessler, Carolin Scheible, Constantin M. Wende, Miyuki Azuma, Pascal Schneider, Lothar Kanz, Ludger Grosse-Hovest, and Helmut R. Salih. "A Fc-Engineered RANK-Fc Fusion Protein Neutralizes Soluble RANK Ligand and Targets Malignant Hematopoietic Cells for NK Cell Reactivity." Blood 114, no. 22 (November 20, 2009): 411. http://dx.doi.org/10.1182/blood.v114.22.411.411.

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Abstract Abstract 411 Bone resorption is commonly associated with aging, but also with certain cancers. Recent studies identified Receptor Activator of NFκB (RANK) ligand (RANKL) and its receptors RANK and osteoprotegerin (OPG) as key regulators of bone resorption. Multiple myeloma (MM) disrupts the balance within this molecule system, and severe bone destruction due to inappropriate osteoclastogenesis is a prominent feature of this disease. Besides MM cells, other malignant hematopoietic cells have also been found to express RANKL at the cell surface and to release this molecule in soluble form (sRANKL). Neutralization of RANKL using RANK-Fc fusion protein or monoclonal antibody (Denosumab/AMG162), which mimics the RANKL-neutralizing endogenous effects of osteoprotegerin, decreases osteolysis in multiple in vivo models and is presently being evaluated as a means to treat both non-malignant and malignant osteolysis. We here confirmed and extended previously published data and report that all investigated MM cell lines (n = 5) as well as primary leukemic cells of CLL patients (n = 12) displayed substantial levels of RANKL mRNA and surface expression. Moreover, we report that substantial levels of sRANKL can be detected in culture supernatants of MM and primary CLL cells, but not in supernatants of healthy PBMC. Next we engineered RANK-Fc fusion proteins with modified affinity to FcγR by mutating amino acids in the Fc portion as previously described (Lazar et al., PNAS 2006; Armour et al., Eur J Immunol 1999). Compared to wildtype RANK-Fc (RANK-Fc-wt), our mutants (S239D/I332E and E233P/L234V/L235A/DeltaG236/A327G/A330S) displayed highly enhanced and abrogated (RANK-Fc-ADCC+ and RANK-Fc-KO, respectively) affinity to FcγRIIIa expressed on NK cells, which play an important role in anti-tumor immunity due to their ability to lyse target cells directly and to mediate antibody-dependent cellular cytotoxicity (ADCC) upon application of therapeutic antibodies. The RANK-Fc-ADCC+ displayed similar capacitiy to neutralize sRANKL compared to the RANK-Fc-KO and the RANK-Fc-wt as revealed by binding competition assays. Next we cultured NK cells with L cells or P815 cells transfected to express RANKL and the parental, RANKL-negative controls in the presence or absence of the different RANK-Fc constructs. Addition of RANK-Fc-KO or RANK-Fc-wt did not substantially alter NK cell reactivity against the target cells. However, presence of the RANK-Fc-ADCC+ dramatically enhanced NK cell cytotoxicity and cytokine production in cultures with the RANKL-expressing target cells (increase from 20% to 89%, E:T ratio 30:1 and 12 pg/ml to 290 pg/ml respectively; both p<0.01, Student's t-test). Neither of the three RANK-Fc proteins altered NK cell cytotoxicity and cytokine production in cultures with the RANKL negative controls demonstrating that the RANK-Fc-ADCC+ specifically induced NK cell reactivity against RANKL-expressing malignant cells. Moreover, treatment with RANK-Fc-ADCC+ also significantly augmented NK cell anti-tumor reactivity in cultures with RANKL-expressing primary CLL cells of patients, and this was observed both in settings using allogenic NK cells and analyzing autologous NK cells among PBMC of the leukemia patients (both p<0.01, Student's t-test). Taken together, our Fc-engineered RANK-Fc-ADCC+ fusion protein may neutralize detrimental effects of sRANKL, can target RANKL-expressing malignant cells for NK cell anti-tumor reactivity and may thus constitute an attractive immunotherapeutic means for treatment of hematopoietic malignancies. Disclosures: No relevant conflicts of interest to declare.

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Journal articles on the topic 'RANKL'

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