To see the other types of publications on this topic, follow the link: Role of OPG-RANK-RANKL.
Journal articles on the topic 'Role of OPG-RANK-RANKL'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Role of OPG-RANK-RANKL.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
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.
Full textAbstract:
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.
2
Zhang, Hao-Wei, Li Peng, Wen-Bo Li, and Ke-Guan Song. "The Role of RANKL/RANK/OPG System in the Canine Model of Hip Periprosthetic Infection Osteolysis." International Journal of Artificial Organs 39, no. 12 (December 2016): 619–24. http://dx.doi.org/10.5301/ijao.5000546.
Full textAbstract:
Purpose We aimed to investigate whether the RANKL/RANK/OPG system is associated with the incidence of periprosthetic osteolysis with septic loosening, and to investigate the differences of RANKL/RANK/OPG system expression in synovial fluid surrounding the normal and septic loosening hip prosthesis in canine models. Methods Twelve healthy adult mongrel canines were divided into two groups: experimental and control. Femoral head and stem replacements were conducted on the right side in both groups. The experimental group received the bacteria fluid intra-articular injection and the other group received the same amount of saline in the same day. The synovial fluid samples were gathered at the 1st, 2nd, 4th, 8th, 12th, 16th and 19th week after the bacteria fluid intra-articular injection for enzyme-linked immunosorbent assay (ELISA), the expression of the RANKL/RANK/OPG system. Results Surgery on all animals was successful. Two dogs were excluded from the analysis of the result because of a surgery infection or death. The ELISA of the synovial fluid revealed that the ratio of RANKL/OPG showed a significant upward trend (p≤0.05) with time in the test group but the ratio of RANKL/OPG in the control group changed slowly over time (p>0.05). The ratio of RANKL/OPG value between the test and control group showed a significant upward trend, but had no statistical difference (p>0.05) over time. Conclusions It could be concluded that the RANKL/RANK/OPG system is correlated with the incidence of periprosthetic osteolysis with septic loosening. Consequently, imbalance RANKL/RANK/OPG system was related to periprosthetic osteolysis with septic loosening.
3
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.
Full text
4
Rochette, Luc, Alexandre Meloux, Eve Rigal, Marianne Zeller, Yves Cottin, and Catherine Vergely. "The Role of Osteoprotegerin and Its Ligands in Vascular Function." International Journal of Molecular Sciences 20, no. 3 (February 6, 2019): 705. http://dx.doi.org/10.3390/ijms20030705.
Full textAbstract:
The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular components and modify gene expression. Cytokine production and activation of their receptors induce mechanisms to recruit monocytes and neutrophils as well as endothelial cells. Data support the role of an increased OPG/RANKL ratio as a possible marker of progression of endothelial dysfunction in metabolic disorders in relationship with inflammatory marker levels. We review the role of the OPG/RANKL/RANK triad in vascular function as well as molecular mechanisms related to the etiology of vascular diseases. The potential therapeutic strategies may be very promising in the future.
5
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.
Full textAbstract:
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.
6
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.
Full textAbstract:
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.
7
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.
Full textAbstract:
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.
8
Geusens, Piet. "The role of RANK ligand/osteoprotegerin in rheumatoid arthritis." Therapeutic Advances in Musculoskeletal Disease 4, no. 4 (March 8, 2012): 225–33. http://dx.doi.org/10.1177/1759720x12438080.
Full textAbstract:
In the complex system of bone remodeling, the receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) pathway is the coupling factor between bone formation and bone resorption. RANKL binds to the RANK receptor of pre-osteoclasts and mature osteoclasts and stimulates their activation and differentiation. The production of RANKL/OPG by osteoblasts is influenced by hormones, growth factors and cytokines, which each have a different effect on the production of RANKL and OPG. Ultimately, the balance between RANKL and OPG determines the degree of proliferation and activity of the osteoclasts. In rheumatoid arthritis (RA), bone erosions are the result of osteoclastic bone resorption at the sites of synovitis, where RANKL expression is also found. Furthermore, magnetic resonance imaging (MRI) bone edema in RA indicates the presence of active inflammation within bone and the presence of osteitis, which is also associated with the expression of RANKL. Bone loss has been documented in the cortical and trabecular bone in the joints of the hand of RA patients. Both synovitis and periarticular bone involvement (osteitis and bone loss) are essential components of RA: they occur early in the disease and both are predictive for the occurrence and progression of bone damage. RANKL knockout mice and mice treated with OPG did not develop focal bone loss, in spite of persistent joint inflammation. Inhibition of osteoclasts by denosumab, a humanized antibody that selectively binds RANKL, has revealed in patients with RA that the occurrence of erosions and periarticular bone loss can be halted, however without affecting synovial inflammation. This disconnect between inflammation and bone destruction opens new ways to separately focus treatment on inflammation and osteoclastogenesis for preventing and/or minimizing the connection between joints and subchondral bone and bone marrow.
9
Gegen, Tana, Yanxia Zhu, Qinnuan Sun, and Benxiang Hou. "Role of interleukin-33 in the clinical pathogenesis of chronic apical periodontitis." Journal of International Medical Research 47, no. 7 (June 20, 2019): 3332–43. http://dx.doi.org/10.1177/0300060519854630.
Full textAbstract:
Objective This study investigated interleukin (IL)-33 expression in chronic apical periodontitis (CAP) lesions and possible relationships with receptor activator of nuclear factor κ-Β ligand (RANKL) and osteoprotegerin (OPG). Methods Inflammatory cell infiltration in CAP lesions and samples of healthy periapical tissue (n = 30 each) was evaluated by hematoxylin and eosin staining. IL-33, RANKL, and OPG expression levels were assessed by immunohistochemistry and real-time PCR. In CAP lesions alone, relationships between mRNA level of IL-33 and mRNA levels of both RANKL and OPG were analyzed by Spearman rank correlation. Results Histological analysis revealed a large number of inflammatory cells in CAP lesions, and immunohistochemistry revealed IL-33-positive cells. There were more IL-33- and RANKL-positive cells in CAP lesions than in healthy periapical tissue, whereas there were fewer OPG-positive cells in CAP lesions than in healthy periapical tissue. In CAP lesions alone, IL-33 mRNA level was negatively correlated with mRNA level of RANKL and positively correlated with mRNA level of OPG. Conclusions IL-33 is highly expressed in CAP lesions, where it is negatively correlated with RANKL and positively correlated with OPG expression. IL-33 may protect against bone resorption via RANKL suppression and OPG induction, and constitutes a potential target for CAP treatment.
10
Kasch, C., A. Osterberg, Thordis Granitzka, T. Lindner, M. Haenle, R. Bader, R. Skripitz, and A. Jonitz-Heincke. "Gene expression analysis of metabolic markers during bone regeneration in a rat model." Osteologie 23, no. 03 (2014): 207–11. http://dx.doi.org/10.1055/s-0037-1620051.
Full textAbstract:
SummaryThe RANK/RANKL/OPG system plays an important role in the regulation of bone metabolism and bony integration around implants. The aim of this study was to analyse gene expression of OPG, RANK, and RANKL in regenerating bone during implant integration. Additionally, the effect of intermittent para - thyroid hormone (PTH) treatment was analysed. A titanium chamber was implanted in the proximal tibiae of 48 female rats. The animals received either human PTH or saline solution (NaCl). After 21 and 42 days, RNA was isolated from tissue adjacent to the implant and expression of RANK, RANKL, and OPG was analysed. After 21 days, very low expression levels of all genes were shown. In contrast, increased gene expression after 42 days was determined. Expression of RANK and RANKL was lower than that for OPG. The lower expression levels after 21 days might be due to still ossifying, fibrotic tissue around the titanium chamber. An increased OPG synthesis rate associated with decreased RANKL expression after 42 days revealed bone-forming processes. Despite significant differences in gene expression between the time points, only slight differences were observed between application of intermittent PTH and NaCl after a period of 42 days.
11
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.
Full textAbstract:
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.
12
Ibrahim, Toni, Laura Mercatali, Marianna Ricci, Emanuela Scarpi, Francesca Fabbri, Chiara Liverani, Stefania Vittoria, Luisa Nicoletti, Rossana Ricci, Patrizia Serra, and Dino Amadori. "Zoledronic acid effect on circulating RANK/RANK-l/OPG axis in cancer patients." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 10615. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.10615.
Full textAbstract:
10615 Background: Bone metastasis disrupts bone integrity through loss of the balance between osteoclastic-mediated osteolysis and osteoblastic osteogenesis. The RANK/RANK-L/OPG axis governs osteoclastogenesis and bone resorption. We evaluated the trend of markers over time. Secondary aims were to study the predictive role of different circulating markers in the response to Zoledronic Acid (ZA) with respect to objective response and to skeletal-related events (SREs). Methods: The study prospectively evaluated levels of RANK, RANKL and OPG transcripts by Real-Time PCR and VEGF and NTX expression by ELISA in the peripheral blood of 49 consecutive patients with advanced breast, prostate or lung cancer (36, 7 and 6, respectively). Enrolled patients were at first diagnosis of bone metastases and had not previously undergone treatment with bisphosphonates. Patients received the standard schedule of ZA (4 mg infusion every 28 days) for about 12 months, undergoing blood tests and instrumental evaluation before the first infusion of ZA and every 4 months thereafter. Results: Median RANKL values after 12 infusions of ZA had decreased by 22% with respect to baseline whereas OPG, had increased by about 96%, with a 56% decrease in the RANKL/OPG ratio. NTX decreased over time (p<0.0001). On the basis of ROC curve analysis, RANKL was the most accurate marker for bone response with an AUC of 0.74 (95% CI 0.54-0.93). No correlations were found between circulating markers and SREs. Conclusions: The present work is one of the few prospective studies carried out on the circulating markers that are potentially associated with bone metastases. Our findings would seem to indicate that ZA decreases osteoclast activity through RANK/RANKL/OPG pathway modulation and that RANKL may play a role in the prediction of objective response to ZA. Confirmation of results is needed in a larger case series.
13
Ruilian, Zhao, Gao Ying, Shen Hongmei, and Guo Lihua. "Exploration of the Effect of Icariin on Nude Mice with Lung Cancer Bone Metastasis via the OPG/RANKL/RANK System." Computational and Mathematical Methods in Medicine 2022 (May 28, 2022): 1–9. http://dx.doi.org/10.1155/2022/2011625.
Full textAbstract:
Epimedium is a traditional Chinese medicine that is most commonly prescribed by practitioners of Chinese medicine for the clinical treatment of malignant tumor bone metastasis. The main component of Epimedium is icariin (ICA). Studies have shown that ICA inhibits bone resorption of osteoclasts through the OPG/RANKL/RANK signaling pathway. Osteoclasts are the only cells in the body that have a bone-destroying capability. The OPG/RANKL/RANK system consists of cytokines that play major roles in osteoclast formation. Therefore, our study selected the OPG/RANKL/RANK system as the research target to investigate the effect of ICA on nude mice with lung cancer bone metastasis. We established the model of bone metastasis in nude mice, intervened the model with icariin and zoledronic acid, and detected the levels of OPG and RANKL by ELISA and western blot. The results showed that ICA had a significant inhibitory effect on bone metastases in nude mice. ICA achieved its antibone metastasis effect in nude mice with lung cancer via inhibiting RANKL expression and simultaneously increasing OPG expression. ICA not only alleviated osteolytic bone destruction caused by bone metastases, but it also reduced weight loss in tumor-bearing nude mice at the late stage of the experiment. The role of ICA in preventing bone metastasis of lung cancer merits further investigation.
14
Obukhovich, A. R., and N. N. Iaskevich. "PATHOPHYSIOLOGICAL ROLE OF OSTEOPROTEGERIN IN ATHEROSCLEROSIS AND DIABETES MELLITUS." Journal of the Grodno State Medical University 20, no. 2 (May 15, 2022): 129–36. http://dx.doi.org/10.25298/2221-8785-2022-20-2-129-136.
Full textAbstract:
Diabetes mellitus is rightly called non-infectious epidemic of the 21st century. At the same time, cardiovascular diseases still remain the leading cause of death in the world. A combination of diabetes mellitus and peripheral arterial disease increases the risk of the lower limb loss and death many times over. There are many concepts concerning the mechanism of development of these diseases. In recent years, there is more and more data evidencing the similarity of the processes of atherosclerosis and osteoporosis development. The connecting link between these processes may be osteoprotegerin (OPG). Information has been obtained on osteoprotegerin as an antiresorptive factor participating in the RANKL-RANK-OPG system. Under pathophysiological conditions, OPG is expressed in the vascular wall, including being found at different stages of atherosclerotic plaque formation. The RANKL-RANK-OPG signaling pathway is involved in the process of bone tissue remodeling. The mechanisms of atherosclerosis and osteoporosis development are similar; nevertheless, they require further study.
15
Liu, Xin-Hua, Alexander Kirschenbaum, Shen Yao, and Alice C. Levine. "Cross-Talk between the Interleukin-6 and Prostaglandin E2 Signaling Systems Results in Enhancement of Osteoclastogenesis through Effects on the Osteoprotegerin/Receptor Activator of Nuclear Factor-κB (RANK) Ligand/RANK System." Endocrinology 146, no. 4 (April 1, 2005): 1991–98. http://dx.doi.org/10.1210/en.2004-1167.
Full textAbstract:
Abstract The osteoprotegerin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) system is the dominant and final mediator of osteoclastogenesis. Abnormalities of this system have been implicated in the pathogenesis of many skeletal diseases. Cyclooxygenase (COX)-2 and prostaglandin (PG)E2, a major eicosanoid product of the COX-2-catalyzed pathway, play key roles in normal bone tissue remodeling. PGE2 exerts its actions by binding and activating the E series of prostaglandin (EP) receptor. Activation of EP2 and EP4 receptors is associated with PGE2-induced osteoclast differentiation. IL-6, a major proinflammatory cytokine, has also been reported to induce osteoclast differentiation. Although interactions between the COX-2/PGE2 and IL-6 systems have been described in bone cells, the mechanisms underlying these cooperative signaling pathways and the possible involvement of the OPG/RANKL/RANK system have not been fully elucidated. We demonstrate that COX-2, PGE2, and IL-6 stimulate osteoblast growth and osteoclast differentiation. Effects on osteoclast differentiation, particularly with IL-6, were most marked when osteoclast precursor cells were grown in coculture with osteoblasts, indicating a possible role of the RANK/RANKL/OPG system. COX-2 and PGE2 stimulated osteoclastogenesis through inhibition of OPG secretion, stimulation of RANKL production by osteoblasts, and up-regulation of RANK expression in osteoclasts. PGE2 stimulated IL-6 secretion by bone cells, whereas COX-2 inhibitors decreased this same parameter. IL-6, in turn, increased PGE2 secretion, COX-2, and EP receptor subtype expression in bone cells. Finally, IL-6 was the mediator of PGE2-induced suppression of OPG production by osteoblasts. These findings provide evidence for cross-talk between the PGE2 and IL-6 signaling enhance osteoclast differentiation via effects on the OPG/RANKL/RANK system in bone cells.
16
Xu, Xiao-Juan, Lin Shen, Yan-Ping Yang, Rui Zhu, Bo Shuai, Cheng-Gang Li, and Man-Xiang Wu. "Serumβ-Catenin Levels Associated with the Ratio of RANKL/OPG in Patients with Postmenopausal Osteoporosis." International Journal of Endocrinology 2013 (2013): 1–7. http://dx.doi.org/10.1155/2013/534352.
Full textAbstract:
Objective. To demonstrate the role of Wnt/β-catenin canonical pathway in postmenopausal osteoporosis by evaluating serumβ-catenin levels in patients with postmenopausal osteoporosis and analyzing their possible relationship with serum OPG, RANKL, the ratio of RANKL/OPG, sclerostin, and bone turnover markers.Methods. 480 patients with postmenopausal osteoporosis and 170 healthy postmenopausal women were enrolled in the study. Serumβ-catenin, OPG, RANKL, and sclerostin levels were measured by enzyme-linked immunosorbent assay. Bone status was assessed by measuring bone mineral density and bone turnover markers. Estradiol levels were also detected.Results. Serumβ-catenin levels were lower in postmenopausal osteoporotic women compared to nonosteoporotic postmenopausal women (26.26±14.81versus39.33±5.47 pg/mL,P<0.001). Serumβ-catenin was positively correlated with osteoprotegerin (r=0.232,P<0.001) and negatively correlated with the ratio of RANKL/OPG, body mass index, and sclerostin (r=-0.128,P=0.005;r=-0.117,P=0.010;r=-0.400,P<0.001, resp.) in patients with postmenopausal osteoporosis.Conclusion. The results indicate that lower serumβ-catenin and concomitantly higher ratio of RANKL/OPG may be involved in the pathogenesis of postmenopausal osteoporosis. Functional communication between RANKL/RANK/OPG system and Wnt pathways plays an important role in postmenopausal osteoporosis.
17
Voronkina, I. V., O. B. Irtyuga, L. V. Smagina, P. E. Adamova, E. V. Zhiduleva, A. B. Malashicheva, Y. S. Sibagatullina, L. P. Kruk, M. L. Gordeev, and O. M. Moiseeva. "Expression of osteoprotegerin and soluble ligand of receptor of kappa-B transcription factor activator in the calcification of aortic valve." Biomeditsinskaya Khimiya 65, no. 1 (January 2019): 57–62. http://dx.doi.org/10.18097/pbmc20196501057.
Full textAbstract:
The mechanism of valve calcification that is the main cause of aortic stenosis formation and progression is not yet clear. In recent years, the role of the OPG/RANKL/RANK system is considered as one of possible variants of pathogenesis of valve calcification. In presented work the differences in OPG and sRANKL levels involved in the calcification processes in tissues of patients with severe aortic stenosis have been examined. The study was performed using three groups of patients: group 1 – patients with aortic stenosis, group 2 – patients with aortic aneurysm, and group 3 – patients with aortic stenosis and aortic dilatation. In patients with aortic stenosis, the level of RANKL was significantly higher, and the level of RANKL was higher in valve than in tissue. The negative correlation between aortic dilatation and RANKL level indicated the lack of RANKL influence on pathogenesis of aortic dilatation. The obtained data confirm the increased expression of RANKL in patients with aortic valve calcification. The results of this study confirm importance of the OPG/RANKL/RANK system in calcification in patients with aortic stenosis. Athough patients of all groups had comparable values of OPG (including patients with aortic dilatation), the RANKL level increased only in patients with aortic stenosis. This suggest involvement of some additional mechanisms influencing the increase of RANKL expression.
18
Lee, Justine C., Lisa Spiguel, Deana S. Shenaq, Ming Zhong, Christian Wietholt, Tong-Chuan He, and Russell R. Reid. "Role of RANK-RANKL-OPG Axis in Cranial Suture Homeostasis." Journal of Craniofacial Surgery 22, no. 2 (March 2011): 699–705. http://dx.doi.org/10.1097/scs.0b013e3182077fbd.
Full text
19
Kichev, Anton, Pascale Eede, Pierre Gressens, Claire Thornton, and Henrik Hagberg. "Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli." Developmental Neuroscience 39, no. 1-4 (2017): 192–206. http://dx.doi.org/10.1159/000464244.
Full textAbstract:
Inflammation in the perinatal brain caused by maternal or intrauterine fetal infection is now well established as an important contributor to the development of perinatal brain injury. Exposure to inflammatory products can impair perinatal brain development and act as a risk factor for neurological dysfunction, cognitive disorders, cerebral palsy, or preterm birth. Pre-exposure to inflammation significantly exacerbates brain injury caused by hypoxic/ischaemic insult. Tumour necrosis factor (TNF) is a family of cytokines largely involved in inflammation signalling. In our previous study, we identified the importance of TNF-related apoptosis-inducing ligand (TRAIL) signalling in the development of perinatal brain injury. We observed a significant increase in the expression levels of a soluble decoy receptor for TRAIL, osteoprotegerin (OPG). Besides TRAIL, OPG is able to bind the receptor activator of the NF-κB (RANK) ligand (RANKL) and inhibit its signalling. The function of the RANK/RANKL/OPG system in the brain has not come under much scrutiny. The aim of this research study was to elucidate the role of RANK, RANKL, and OPG in microglial responses to the proinflammatory stimuli lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid (Poly I:C). Here, we show that RANK signalling is important for regulating the activation of the BV2 microglial cell line. We found that LPS treatment causes a significant decrease in the expression of RANK in the BV2 cell line while significantly increasing the expression of OPG, Toll-like receptor (TLR)3, and the adaptor proteins MyD88 and TRIF. We found that pretreatment of BV2 cells with RANKL for 24 h before the LPS or Poly I:C exposure decreases the expression of inflammatory markers such as inducible nitric oxide synthase and cyclooxygenase. This is accompanied by a decreased expression of the TLR adaptor proteins MyD88 and TRIF, which we observed after RANKL treatment. Similar results were obtained in our experiments with primary mouse microglia. Using recently developed CRISPR/Cas9 technology, we generated a BV2 cell line lacking RANK (RANK-/- BV2). We showed that most effects of RANKL pretreatment were abolished, thereby proving the specificity of this effect. Taken together, these findings suggest that RANK signalling is important for modulating the inflammatory activation of microglial cells to a moderate level, and that RANK attenuates TLR3/TLR4 signalling.
20
Andjelkovic, Zlatibor, Vuka Katic, Dragan Mihajlovic, Vesna Zivkovic, Aleksandar Petrovic, and Dusan Lalosevic. "Osteoprotegerin: A neutralizing receptor, protector of bones and a potential antiresorptive agent." Medical review 58, no. 7-8 (2005): 362–67. http://dx.doi.org/10.2298/mpns0508362a.
Full textAbstract:
Introduction The receptor activator of NF-B ligand (RANKL), expressed on the surface of osteoblasts and stromal cells in the bone marrow, plays an essential role in the formation and differentiation of osteoclasts and bone resorption. RANKL binds to its functional receptor, receptor activator of NF-B (RANK), expressed as a transmembrane heterotrimer on the surface of hematopoietic osteoclasts progenitors and mature osteoclasts. RANKL-RANK interaction is inhibited by soluble receptor-osteoprotegerin. Osteoprotegerin Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor superfamily, acts as a natural decoy receptor that blocks the interaction between RANKL and RANK. The balance between RANKL and osteoprotegerin is of major importance in bone homeostasis, Osteoprotegerin inhibits differentiation and formation of osteoclasts and induces apoptosis of osteoclasts. OPG knock-out mice develop severe osteoporosis. In contrast, overexpression of OPG in transgenic mice causes osteopetrosis. Osteoprotegerin as a therapeutic agent Antiresorptive activity of osteoprotegerin is proved in numerous experimental models. Osteoprotective effect of osteoprotegerin has recently been proved in postmenopausal women with osteoporosis as well as in patients with multiple myeloma and osteolytic metastases of breast cancer. Conclusion Osteoprotegerin is a potent antiosteoclast agent that may prove useful in the treatment of bone disorders with net bone loss, such as postmenopausal osteoporosis and cancer metastases.
21
Ohazama, A., J. M. Courtney, and P. T. Sharpe. "Opg, Rank, and Rankl in Tooth Development: Co-ordination of Odontogenesis and Osteogenesis." Journal of Dental Research 83, no. 3 (March 2004): 241–44. http://dx.doi.org/10.1177/154405910408300311.
Full textAbstract:
Osteoprotegerin (OPG), receptor activator of nuclear factor-κB (RANK), and RANK ligand (RANKL) are mediators of various cellular interactions, including bone metabolism. We analyzed expression of these three genes during murine odontogenesis from epithelial thickening to cytodifferentiation stages. Opg showed expression in the thickening and bud epithelium. Expression of Opg and Rank was observed in both the internal and the external enamel epithelium as well as in the dental papilla mesenchyme. Although Rankl expression was not detected in tooth epithelium or mesenchyme, it was expressed in pre-osteogenic mesenchymal cells close to developing tooth germs. All three genes were detected in developing dentary bone at P0. The addition of exogenous OPG to explant cultures of tooth primordia produced a delay in tooth development that resulted in reduced mineralization. We propose that the spatiotemporal expression of these molecules in early tooth and bone primordia cells has a role in co-ordinating bone and tooth development.
22
Anastasilakis, Athanasios D., Marina Tsoli, Gregory Kaltsas, and Polyzois Makras. "Bone metabolism in Langerhans cell histiocytosis." Endocrine Connections 7, no. 7 (July 2018): R246—R253. http://dx.doi.org/10.1530/ec-18-0186.
Full textAbstract:
Langerhans cell histiocytosis (LCH) is a rare disease of not well-defined etiology that involves immune cell activation and frequently affects the skeleton. Bone involvement in LCH usually presents in the form of osteolytic lesions along with low bone mineral density. Various molecules involved in bone metabolism are implicated in the pathogenesis of LCH or may be affected during the course of the disease, including interleukins (ILs), tumor necrosis factor α, receptor activator of NF-κB (RANK) and its soluble ligand RANKL, osteoprotegerin (OPG), periostin and sclerostin. Among them IL-17A, periostin and RANKL have been proposed as potential serum biomarkers for LCH, particularly as the interaction between RANK, RANKL and OPG not only regulates bone homeostasis through its effects on the osteoclasts but also affects the activation and survival of immune cells. Significant changes in circulating and lesional RANKL levels have been observed in LCH patients irrespective of bone involvement. Standard LCH management includes local or systematic administration of corticosteroids and chemotherapy. Given the implication of RANK, RANKL and OPG in the pathogenesis of the disease and the osteolytic nature of bone lesions, agents aiming at inhibiting the RANKL pathway and/or osteoclastic activation, such as bisphosphonates and denosumab, may have a role in the therapeutic approach of LCH although further clinical investigation is warranted.
23
Hamoudi, Dounia, Zineb Bouredji, Laetitia Marcadet, Hideo Yagita, Louis-Bénédict Landry, Anteneh Argaw, and Jérôme Frenette. "Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice." Human Molecular Genetics 29, no. 3 (January 15, 2020): 483–94. http://dx.doi.org/10.1093/hmg/ddz312.
Full textAbstract:
Abstract Bone and muscle are tightly coupled and form a functional unit under normal conditions. The receptor-activator of nuclear factor κB/receptor-activator of nuclear factor κB ligand/osteoprotegerin (RANK/RANKL/OPG) triad plays a crucial role in bone remodeling. RANKL inhibition by OPG prevents osteoporosis. In contrast, the absence of OPG results in elevated serum RANKL and early onset osteoporosis. However, the impacts of OPG deletion on muscle structure and function are unknown. Our results showed that 1-, 3- and 5-month-old Opg−/− mice have reduced tibial and femoral bone biomechanical properties and higher levels of circulating RANKL. OPG-deficient mice displayed reduced locomotor activity and signs of muscle weakness at 5 months of age. Furthermore, OPG deficiency did not affect the skeletal muscles in 1- and 3-month-old mice. However, it impaired fast-twitch EDL but not slow-twitch Sol muscles in 5-month-old Opg−/− mice. Moreover, 5-month-old Opg−/− mice exhibited selective atrophy of fast-twitch-type IIb myofibers, with increased expression of atrophic proteins such as NF-kB, atrogin-1 and MuRF-1. We used an in vitro model to show that RANKL-stimulated C2C12 myotubes significantly increased the expression of NF-kB, atrogin-1 and MuRF-1. A 2-month anti-RANKL treatment starting at 3 months of age in Opg−/− mice improved voluntary activity, the ex vivo maximum specific force (sP0) of EDL muscles, and whole limb grip force performance and rescued the biomechanical properties of bone. In conclusion, the deletion of OPG and the disruption of the RANKL/OPG balance induced osteoporosis as well as the selective weakness and atrophy of the powerful fast-twitch IIb myofibers, which was partly alleviated by an anti-RANKL treatment.
24
Luo, Wei, Yanqiu Song, Jing Wang, Xia Yang, Zuocheng Li, and Hongliang Cong. "The Effect of Osteoprotectin (OPG)/Receptor Activator of Nuclear Factor-κB Ligand (RANKL)/Receptor Activator of Nuclear Factor-κB (RANK) Gene Methylation on Aortic Valve Calcified." BioMed Research International 2022 (August 12, 2022): 1–10. http://dx.doi.org/10.1155/2022/1592576.
Full textAbstract:
To evaluate the effect of the methylation of osteoprotectin (OPG)/receptor activator of nuclear factor-κB ligand (RANKL)/receptor activator of nuclear factor-κB (RANK) pathway on aortic valve calcification, the aortic valve tissue was collected from 38 aortic stenosis (AS) patients who underwent valve replacement. OPG and RANKL gene methylation, RT-PCR, and ELISA were performed. Hematoxylin-eosin staining (HE), alizarin red-S staining, and immunohistochemically staining of OPG, RANKL, and CD68 were simultaneously performed. The patients were divided into noncalcified group ( n = 21 ) and calcified group ( n = 17 ). The methylation rate of OPG gene in noncalcified group was higher than that in calcified group ( P = 0.027 ). The methylation degree of RANKL gene was generally lower, but the noncalcified group was still higher than that in the calcified group ( P = 0.025 ). RT-PCR analysis showed that the mRNA expression of OPG and RANKL was higher in calcified group than in noncalcified group ( P = 0.007 and P = 0.036 , respectively), and the mRNA expression was negatively correlated with the gene methylation rate. The protein expression of OPG and RANKL was detected by immunohistochemistry and ELISA, showing significantly increased in calcified group ( P = 0.004 and P = 0.042 , respectively). Soluble RANKL (sRANKL) in CD68-positive group was significantly different from that in negative group ( 0.1243 ± 0.0321 vs 0.0984 ± 0.0218 pg/mL, P = 0.007 ). There was no significant difference in OPG value between positive group ( 1.9411 ± 0.4554 ng/mL) and negative group ( 1.8422 ± 0.5218 ng/mL, P = 0.587 ). In conclusion, the degree of methylation of OPG and RANKL genes may play an important role in regulating valve calcification in AS patients.
25
Kirschenbaum, Alexander, Sudeh Izadmehr, Shen Yao, Kieley L. O’Connor-Chapman, Alan Huang, Elias M. Gregoriades, Shoshana Yakar, and Alice C. Levine. "Prostatic Acid Phosphatase Alters the RANKL/OPG System and Induces Osteoblastic Prostate Cancer Bone Metastases." Endocrinology 157, no. 12 (October 26, 2016): 4526–33. http://dx.doi.org/10.1210/en.2016-1606.
Full textAbstract:
Prostate cancer (PCa) is unique in its tendency to produce osteoblastic (OB) bone metastases. There are no existing therapies that specifically target the OB phase that affects 90% of men with bone metastatic disease. Prostatic acid phosphatase (PAP) is secreted by PCa cells in OB metastases and increases OB growth, differentiation, and bone mineralization. The purpose of this study was to investigate whether PAP effects on OB bone metastases are mediated by autocrine and/or paracrine alterations in the receptor activator of nuclear factor κ-B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) system. To investigate whether PAP modulated these factors and altered the bone reaction, we knocked down PAP expression in VCaP cells and stably overexpressed PAP in PC3M cells, both derived from human PCa bone metastases. We show that knockdown of PAP in VCaP cells decreased OPG while increasing RANK/RANKL expression. Forced overexpression of PAP in PC3M cells had the inverse effect, increasing OPG while decreasing RANK/RANKL expression. Coculture of PCa cells with MC3T3 preosteoblasts also revealed a role for secretory PAP in OB-PCa cross talk. Reduced PAP expression in VCaP cells decreased MC3T3 proliferation and differentiation and reduced their OPG expression. PAP overexpression in PC3M cells altered the bone phenotype creating OB rather than osteolytic lesions in vivo using an intratibial model. These findings demonstrate that PAP secreted by PCa cells in OB bone metastases increases OPG and plays a critical role in the vicious cross talk between cancer and bone cells. These data suggest that inhibition of secretory PAP may be an effective strategy for PCa OB bone lesions.
26
Assmann, Gunter, Stefanie Keller, Mei Fang Ong, Sandra Grass, Michael Pfreundschuh, and Stefan Wieczorek. "Genetic Polymorphisms of the RANKL and OPG Genes Associated with Myeloma." Blood 118, no. 21 (November 18, 2011): 2911. http://dx.doi.org/10.1182/blood.v118.21.2911.2911.
Full textAbstract:
Abstract Abstract 2911 The bone disease in myeloma is the result of the complex interactions between myeloma cells and the bone marrow osteoclasts plus other accessory cells and microenvironmental components. The receptor activator of NfkappaB (RANK) and osteoprotegerin (OPG) cascade system have been reported to be an essential pathway in the osteoclastogenesis. Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are supposed to play a role in the susceptibility of myeloma. In the present case control study genomic DNA was obtained in 217 myeloma patients including smoldering myeloma (age: mean 62, 33–88) and 516 healthy controls (healthy blood donors, HC; age mean: 44, 18–65). We studied six single-nucleotide-polymorphisms (SNPs) in the genes of RANK (2 SNPs, rs1805034, rs35211496), OPG (2 SNPs, rs3102735, rs2073618), and of RANKL (2 SNPs, rs9533156, rs2277438) using TaqMan assay guided polymerase chain reaction for the respective SNPs. The genotype and allelic frequencies comparing myeloma patients with HC were analyzed with χ2 test for 2×3 and 2×2 tables, respectively. The genotype distributions of the SNP rs2277438 in the RANKL gene and SNP rs3102735 in the OPG gene differed highly significantly (p=0.0001 and p=0.005, respectively) between myeloma patients and HC (table 1). No significantly increased risk was detected in the other SNP analyzed in the study. A subgroup analysis of the myeloma patients stratified into beta2 microglobulin levels lower or higher than 3.5 mg/l showed lower values to be significantly associated with the minor allele of the SNP rs3102735 in the OPG gene (major vs. minor allele in myeloma vs. HC: 77/23% vs. 89/11%; OR 2.49; CI 1.38–4.49). Further stratification into gender, serum calcium levels, hemoglobin values at diagnosis showed no differences.Table 1Myeloma patientsHealthy controls (HC)OR (CI)pRANKL rs2277438Allelen = 434 (%)n = 1024 (%)1324 (75)860 (84)1.7790.00012110 (25)164 (16)(1.373–2.341)Genotypen = 217 (%)n = 512 (%)11132 (61)360 (70)0.00011260 (28)140 (27)2225 (12)12 (2)OPG rs 3102735Allelen = 420 (%)n = 1028 (%)167 (16)109 (11)1.6000.0052353 (84)919 (89)(1.153–2.222)Genotypen = 210 (%)n = 514 (%)119 (4)5 (1)0.0051249 (23)99 (19)22152 (72)410 (80)RANK = receptor activator of NfkappaB, RANKL = receptor activator of NfkappaB ligand, OPG = osteoprotegerin, OR = odds ratio, CI = confidence intervals 95% To the best of our knowledge, this is the first study reporting a highly significant association of the SNP rs2277438 of the RANKL gene and the SNP rs3102735 in the OPG gene, respectively, with the susceptibility to develop myeloma in the Caucasian population. Both SNPs are associated with an increased risk for myeloma. However, myeloma patients carrying the minor allele of OPG SNP rs3102735 developed lower levels of the proliferation marker beta2 microglobulin. The impact of the OPG SNP rs3102735 (location: promoter region, chromosome 8q24) or of the SNP rs2277438 located in intron 1 (chromosome 13q14.11), a potentially regulatory region of the RANKL gene, on the regulation of RANKL expression is unclear. Disclosures: No relevant conflicts of interest to declare.
27
Lee, Justine C., Lisa Spiguel, Deana Shenaq, Ming Zhong, Christian Wietholt, Tong-Chuan He, and Russell R. Reid. "The Role of RANK-RANKL-OPG Axis in Cranial Suture Homeostasis." Plastic and Reconstructive Surgery 126 (October 2010): 100. http://dx.doi.org/10.1097/01.prs.0000388825.27037.c3.
Full text
28
Amin, Negin, Virginia Boccardi, Mohsen Taghizadeh, and Sadegh Jafarnejad. "Probiotics and bone disorders: the role of RANKL/RANK/OPG pathway." Aging Clinical and Experimental Research 32, no. 3 (May 22, 2019): 363–71. http://dx.doi.org/10.1007/s40520-019-01223-5.
Full text
29
Kim, Ju, Yun Ji Shin, Chung Hyeon Choe, In Sun Park, Kang-Yeol Yu, and Yong-Suk Jang. "Possible involvement of transmembrane protein 173 in RANKL-induced osteoclastogenesis (P3012)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 114.7. http://dx.doi.org/10.4049/jimmunol.190.supp.114.7.
Full textAbstract:
Abstract Osteoclasts play a central role in bone development and remodeling via the resorption of bone and are thus important mediators of bone loss, which leads to osteoporosis. In this research, we investigated the effect of Tmem173 on RANKL-induced osteoclastogenesis via the study of osteoclast differentiation associated gene expression, TRAP activity and NO on Tmem173 overexpressed RAW264.7 cells. The mRNA levels of c-Fos, NFATc1, TRAP and TRAP activity were decreased in Tmem173 overexpressed RAW264.7 cells stimulated by RANKL. In addition, we observed down-regulation NO production and the mRNA levels of NO associated factors such as COX-2 and iNOS. Interestingly, we discovered up-regulation of the Tmem173 by osteoprotegerin (OPG) on Tmem173 overexpressed RAW264.7 cells. OPG prevents interaction of RANKL to RANK by competitive binding to RANKL. These results provide new additional information that Tmem173 played a regulatory role in RANKL-mediated osteoclast differentiation.
30
Thomas, GP, SU Baker, JA Eisman, and EM Gardiner. "Changing RANKL/OPG mRNA expression in differentiating murine primary osteoblasts." Journal of Endocrinology 170, no. 2 (August 1, 2001): 451–60. http://dx.doi.org/10.1677/joe.0.1700451.
Full textAbstract:
Osteoblast-osteoclast coordination is critical in the maintenance of skeletal integrity. The modulation of osteoclastogenesis by immature cells of the osteoblastic lineage is mediated through receptor activator of NF kappa B (RANK), its ligand RANKL, and osteoprotegerin (OPG), a natural decoy receptor for RANKL. Here, the expression of OPG and RANKL in primary mouse osteoblastic cultures was investigated to determine whether the osteoclastogenic stimulus depended on the stage of osteoblastic differentiation and the presence of the calciotrophic hormone 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)). OPG mRNA expression was increased in osteoblastic cultures after the onset of mineralisation relative to less mature cultures, but did not alter in response to 1,25-(OH)(2)D(3) treatment. In contrast, basal RANK L mRNA expression did not change during differentiation but was significantly enhanced by 1,25-(OH)(2)D(3) treatment at all times. The stimulatory effects of 1,25-(OH)(2)D(3) on RANKL were lessened in more mature cultures, however. The RANKL/OPG ratio, an index of osteoclastogenic stimulus, was therefore increased by 1,25-(OH)(2)D(3) treatment at all stages of osteoblastic differentiation, but to a lesser degree in cultures after the onset of mineralisation. Thus the 1,25-(OH)(2)D(3)-driven increase in osteoclastogenic potential of immature osteoblasts appears to be mediated by increased RANKL mRNA expression, with mature osteoblasts having relatively decreased osteoclastogenic activity due to increased OPG mRNA expression. These findings suggest a possible mechanism for the recently proposed negative regulatory role of mature osteoblasts on osteoclastogenesis and indicate that the relative proportions of immature and mature osteoblasts in the local microenvironment may control the degree of resorption at each specific bone site.
31
Assmann, Gunter, Ingolf Juhasz-Boess, Frank Gruenhage, Stefan Graeber, Stefan Wieczorek, Michael Pfreundschuh, Erich-Franz Solomayer, and Jasmin Teresa Ney. "Genetic polymorphisms of the OPG gene associated with breast cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 1523. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1523.
Full textAbstract:
1523 Background: The receptor activator of NfkappaB (RANK) and osteoprotegerin (OPG) cascade system have been reported to play a role in the pathogenesis of breast cancer (BC). Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are supposed to play a role in the susceptibility of breast cancer. Methods: In the present case-control study genomic DNA was obtained from 307 BC patients (age: median 56) and 396 healthy female controls (healthy blood donors, HC; age median: 45). We studied six single nucleotide polymorphisms (SNPs) in the genes coding for RANK (2 SNPs, rs1805034, rs35211496), OPG (2 SNPs, rs3102735, rs2073618), and RANKL (2 SNPs, rs9533156, rs2277438) using TaqMan assay-guided PCR for the respective SNPs. The genotype and allelic frequencies comparing BC with HC were analyzed with χ2 test for 2x3 and 2x2 tables, respectively. Results: The genotype distributions as well as the allelic frequencies of the SNP rs3102735 in the OPG gene differed significantly (p=0.006 and p=0.019, respectively) between BC patients and HC; the genotypes containing the minor allele were more frequent in BC patients (table). In the OPG SNP rs2073618 the minor allele C was significantly less frequent in BC patients compared to HC (43.8 vs. 49.7%; OR: 0.788; p=0.031). In addition, BC patients carried less frequently the homozygous genotype of the minor allele compared to major allele (18.6 vs. 23.9%, p=0.083). No significant risk was detected for the other SNPs investigated in this study. Conclusions: This is the first study reporting a significant association of the SNP rs3102735 in the OPG gene with the susceptibility to develop BC in the Caucasian population. The minor allele C of OPG SNP rs2073618, however, seems to be protective against BC disease. The impact of the OPG SNP rs3102735 (location: 5`near region, chromosome 8q24) and of the OPG SNP rs2073618 (a missense SNP, leading to amino acid exchanges Leu3Asn) on the pathogenesis of BC are unclear. [Table: see text]
32
Popova, Velichka. "A STUDY OF SERUM LEVELS OF RANKL AND OPG INPATIENTS WITH ACUTE CORONARY SYNDROME WITH AND WITHOUT PSORIATIC ARTHRITIS." Knowledge International Journal 28, no. 2 (December 10, 2018): 489–94. http://dx.doi.org/10.35120/kij2802489p.
Full textAbstract:
Receptor Activator of Nuclear Factor Kappa B Ligand (RANKL) is a member of the tumor necrosis factor alpha(TNFa) family.It signals by its RANK receptor on monocyte/macrophage progenitors and stimulates the formation of bone-resorbing osteoclasts [1]. In psoriatic arthritis (PsA) RANKL is produced by activated Th17 cells, synovial fibroblasts, macrophages, dendritic cells and activated lymphocytes [2,3]. These are cells involved in systemic and local inflammation and atherogenesis.Osteoprotegerin (OPG) is a glycoprotein first described in 1997 by Simonet et al. [1]who refer to it as a bone-protecting protein. OPG is a new member of theTNFa superfamily,a soluble receptor which acts as a decoy for RANKL and other ligands. It is also synthesized in many other tissues such as kidney, placenta, bones, vessels, lungs, and vascular structures. It circulates in serum and in plasma, although the concentration is much lower than locally in the bone and arterial tissue[4,5,6]. It has been found that vascular smooth muscle cellssynthesize it as a result of various stimuli. OPG also protects large blood vessels from medialcalcification[7].The biological effect of OPG is to oppose RANKL and thus prevent subsequent stimulation of the receptor, therefore the level of OPG increases and acts as a mechanism of self-defense.The role of RANKL and OPG in cardiovascular disease is still insufficiently defined and remains contradictory[8]. Also, the relationship between high serum levels of OPG in acute coronary syndrome( ACS) and their relation to inflammatory joint disease (IJD) is still discussed [9]. Evidence has been collected demonstrating the active involvement of RANKL and OPG in vascular pathology, including atherogenesis, arterial calcification and plaque instability.Epidemiological studies show that elevated OPG levels in the circulation have a prognostic function in cardiovascular mortality and morbidity and may be a serum prognostic marker for future vascular events. On the other hand, the involvement ofRANKL and OPG in the pathogenesis of local and systemic inflammation in ACS and IJD could link them to the amplification of cardiovascular risk and the severity of acute coronary syndromes, especially in patients with PsA. It is possible that the serum OPG level is increased in response to vascular wall damage and ongoing inflammation process within the atherosclerotic plaque lesion as a component of a complex compensatory mechanism in which RANKL plays a central role [11]. Serum OPG levels may be indicative of persistent damage of endothelial cells as well as the activation of VSMCs in advanced atherosclerotic plaque lesion.Together with other inflammatory mediators, RANKL and OPG can play a crucial role in the formation of the atherosclerotic plaque, its maturation and calcification[12, 13]. The present study aimed to examine and compare levels of sRANKL and sOPG in patients with ACS, divided into two groups, with and without PsA.Associations with cardiovascular mortality risk measured by the Global Registry of Acute Coronary Events (GRACE) were sought.ACS patients with and without PsA were compared in relation to sRANKL (24 and 48hrs) and sOPG (24 and 48hrs) to explore the effect of ACS.
33
Liu, Xinhong, Jiazhuang Zheng, Fang Li, Ruokun Yi, Jianfei Mu, Fang Tan, and Xin Zhao. "Lactobacillus Plantarum HFY15 Helps Prevent Retinoic Acid-Induced Secondary Osteoporosis in Wistar Rats." Evidence-Based Complementary and Alternative Medicine 2020 (September 23, 2020): 1–10. http://dx.doi.org/10.1155/2020/2054389.
Full textAbstract:
A rat model of secondary osteoporosis was constructed using retinoic acid as an inducer, and the genes, proteins, and bone mass of the rats were analyzed. qPCR detection of the Wnt/β-catenin and OPG/RANK/RANKL signaling pathway-related gene expression levels showed that Lactobacillus plantarum HFY15 played a positive role in regulating both pathways. HFY15 significantly increased β-catenin, Lrp5, Lrp6, Wnt10b, OPG, RANKL, and Runx2 expression and downregulated DKK1, RANK, CTSK, TRACP, and ALP expression. Enzyme-linked immunosorbent assays further confirmed the qPCR results. Tartrate-resistant acid phosphatase staining showed that HFY15 slowed retinoic acid-induced osteoclast formation. Microcomputed tomography showed that HFY15 reduced trabecular separation and increased the percent bone volume, trabecular numbers, trabecular thickness, and bone mineral density in the rats in vivo. These findings indicate that HFY15 may help prevent retinoic acid-induced secondary osteoporosis in vivo.
34
Yureneva, S. V. "Osteoprotegerin and its ligands for regulating the osteal resorption: experimental and clinical application aspects under estrogen deficiency conditions." Journal of obstetrics and women's diseases 53, no. 1 (January 14, 2004): 107–10. http://dx.doi.org/10.17816/jowd87168.
Full textAbstract:
Modem conceptions concerning the role of OPG-RANK-RANKL system in a local paracrinic mechanism of the regulation of osteoclastogenesis and osteal resorption processes are presented in this article. Here, results of the first clinical researches of prognostic signification of ORG determinations for estimating disruption manifestations in osteal metabolism under estrogen deficiency conditions as well as data on the OPG use as an anti-resorbable agent at the treatment of post-menopausal osteoporosis.
35
Senba, Masachika, Kioko Kawai, and Naoki Mori. "Pathogenesis of Metastatic Calcification and Acute Pancreatitis in Adult T-Cell Leukemia under Hypercalcemic State." Leukemia Research and Treatment 2012 (December 1, 2012): 1–9. http://dx.doi.org/10.1155/2012/128617.
Full textAbstract:
Human T-cell leukemia virus type-1 (HTLV-1) is the causative agent of adult T-cell leukemia (ATL). Hypercalcemia is common in patients with ATL. These patients rarely develop metastatic calcification and acute pancreatitis. The underlying pathogenesis of this condition is osteoclast hyperactivity with associated overproduction of parathyroid hormone-related protein, which results in hypercalcemia in association with bone demineralization. The discovery of the osteoclast differentiation factor receptor activator of nuclear factor-κB ligand (RANKL), its receptor RANK, and its decoy receptor osteoprotegerin (OPG), enhanced our understanding of the mechanisms of ATL-associated hypercalcemia. Macrophage inflammatory protein-1-α, tumor necrosis factor-α, interleukin-1, and interleukin-6 are important molecules that enhance the migration and differentiation of osteoclasts and the associated enhanced production of RANKL for osteoblast formation. In this paper, we focus on metastatic calcification and acute pancreatitis in ATL, highlighting recent advances in the understanding of the molecular role of the RANKL/RANK/OPG system including its interaction with various cytokines and calciotropic hormones in the regulation of osteoclastogenesis for bone resorption in hypercalcemic ATL patients.
36
Tobeiha, Mohammad, Mohammed H. Moghadasian, Negin Amin, and Sadegh Jafarnejad. "RANKL/RANK/OPG Pathway: A Mechanism Involved in Exercise-Induced Bone Remodeling." BioMed Research International 2020 (February 20, 2020): 1–11. http://dx.doi.org/10.1155/2020/6910312.
Full textAbstract:
Bones as an alive organ consist of about 70% mineral and 30% organic component. About 200 million people are suffering from osteopenia and osteoporosis around the world. There are multiple ways of protecting bone from endogenous and exogenous risk factors. Planned physical activity is another useful way for protecting bone health. It has been investigated that arranged exercise would effectively regulate bone metabolism. Until now, a number of systems have discovered how exercise could help bone health. Previous studies reported different mechanisms of the effect of exercise on bone health by modulation of bone remodeling. However, the regulation of RANKL/RANK/OPG pathway in exercise and physical performance as one of the most important remodeling systems is not considered comprehensive in previous evidence. Therefore, the aim of this review is to clarify exercise influence on bone modeling and remodeling, with a concentration on its role in regulating RANKL/RANK/OPG pathway.
37
Terpos, Evangelos, Richard Szydlo, Jane F. Apperley, Evdoxia Hatjiharissi, Marianna Politou, John Meletis, Nora Viniou, Xenophon Yataganas, John M. Goldman, and Amin Rahemtulla. "Soluble receptor activator of nuclear factor κB ligand–osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index." Blood 102, no. 3 (August 1, 2003): 1064–69. http://dx.doi.org/10.1182/blood-2003-02-0380.
Full textAbstract:
Abstract Interaction between receptor activator of nuclear factor κB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and β2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.
38
Filipowska, Joanna K., Nagesha G. Kondegowda, and Rupangi C. Vasavada. "LGR4 and Its Extracellular Domain as Novel Regulators of ß-Cell Survival and Proliferation." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A321—A322. http://dx.doi.org/10.1210/jendso/bvab048.656.
Full textAbstract:
Abstract Our lab has shown that RANK (Receptor activator of the NF-κB) by interacting with its ligand, RANKL, inhibits ß-cell proliferation and survival; which can be reversed by Osteoprotegerin (OPG). Recently, the G protein-coupled receptor LGR4 (leucine-rich repeat-containing G protein-coupled receptor 4), which binds R-spondin (RSPO), was identified as a novel receptor for RANKL in osteoclast precursor cells. Thus, RANKL can bind two distinct receptors, RANK and LGR4 in osteoclasts, leading to opposite effects on osteoclastogenesis. LGR4 is expressed in rodent and human ß-cells, but the role of this receptor in ß-cells remains unknown. We postulated that LGR4 through its interaction with RANKL is involved in regulating ß-cell survival and proliferation. Our data indicate expression of specific LGR4 family members, Lgr4, Rank, Rankl, is modulated by stressors, such as cytokines, ER stress, diabetes and aging, in INS1 cells, rodent and human islets. Knocking down Lgr4 in INS1 cells or rodent islets has no significant effect on ß-cell proliferation but is detrimental for ß-cell survival in basal and cytokine-stimulated conditions. We also propose that the soluble extracellular domain of LGR4 (LGR4-ECD), which binds to its ligands (RSPO/RANKL), holds therapeutic potential like OPG, by inhibiting the interaction between RANKL/RANK. At 200ng/ml LGR4-ECD significantly enhances young adult (8-12-week-old) and aged (1.y.o.) rodent ß-cell proliferation, as well as human ß-cell proliferation, in islets from not only control subjects (45±17 y.o.), but also with Type 2 diabetes (48±7 y.o.). Additionally, LGR4-ECD significantly promotes mouse and human ß-cell survival against cytokine-induced cell death. Future studies will determine the physiological role of LGR4 and the therapeutic potential of LGR4-ECD on the beta cell in vivo in basal conditions and in the setting of diabetes. Acknowledgements: Funding: JDRF postdoctoral fellowship # 3-PDF-2020-936-A-N to JF; Human Islets: IIDP
39
Bocelli-Tyndall, Chiara, Emanuele Trella, Audrey Frachet, Paul Zajac, Dennis Pfaff, Jeroen Geurts, Stefan Heiler, et al. "FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells." Annals of the Rheumatic Diseases 74, no. 1 (November 18, 2013): 260–66. http://dx.doi.org/10.1136/annrheumdis-2013-204235.
Full textAbstract:
ObjectiveHuman bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1β and IFNγ.MethodsRANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1β and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR.ResultsIn hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1β and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1β induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1β through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1β in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts.ConclusionsRANKL expression and IL1β regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1β and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.
40
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.
Full textAbstract:
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.
41
Pivonka, Peter, Jan Zimak, David W. Smith, Bruce S. Gardiner, Colin R. Dunstan, Natalie A. Sims, T. John Martin, and Gregory R. Mundy. "Theoretical investigation of the role of the RANK–RANKL–OPG system in bone remodeling." Journal of Theoretical Biology 262, no. 2 (January 2010): 306–16. http://dx.doi.org/10.1016/j.jtbi.2009.09.021.
Full text
42
Kovács, Béla, Enikő Vajda, and Előd Ernő Nagy. "Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis." International Journal of Molecular Sciences 20, no. 18 (September 19, 2019): 4653. http://dx.doi.org/10.3390/ijms20184653.
Full textAbstract:
Cartilage and the bordering subchondral bone form a functionally active regulatory interface with a prominent role in osteoarthritis pathways. The Wnt and the OPG-RANKL-RANK signaling systems, as key mediators, interact in subchondral bone remodeling. Osteoarthritic osteoblasts polarize into two distinct phenotypes: a low secretory and an activated, pro-inflammatory and anti-resorptive subclass producing high quantities of IL-6, PGE2, and osteoprotegerin, but low levels of RANKL, thus acting as putative effectors of subchondral bone sclerosis. Wnt agonists, Wnt5a, Wisp-1 initiate excessive bone remodeling, while Wnt3a and 5a simultaneously cause loss of proteoglycans and phenotype shift in chondrocytes, with decreased expression of COL2A, aggrecan, and Sox-9. Sclerostin, a Wnt antagonist possesses a protective effect for the cartilage, while DKK-1 inhibits VEGF, suspending neoangiogenesis in the subchondral bone. Experimental conditions mimicking abnormal mechanical load, the pro-inflammatory milieu, but also a decreased OPG/RANKL ratio in the cartilage, trigger chondrocyte apoptosis and loss of the matrix via degradative matrix metalloproteinases, like MMP-13 or MMP-9. Hypoxia, an important cofactor exerts a dual role, promoting matrix synthesis via HIF-1α, a Wnt silencer, but turning on HIF-2α that enhances VEGF and MMP-13, along with aberrant collagen expression and extracellular matrix deterioration in the presence of pro-inflammatory cytokines.
43
Greco, Tommaso, Antonio Mascio, Chiara Comisi, Chiara Polichetti, Silvio Caravelli, Massimiliano Mosca, Nicola Mondanelli, Elisa Troiano, Giulio Maccauro, and Carlo Perisano. "RANKL-RANK-OPG Pathway in Charcot Diabetic Foot: Pathophysiology and Clinical-Therapeutic Implications." International Journal of Molecular Sciences 24, no. 3 (February 3, 2023): 3014. http://dx.doi.org/10.3390/ijms24033014.
Full textAbstract:
Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-κB ligand (RANKL)-Receptor Activator of NF-κB (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO.
44
Kang, J. H., H. M. Ko, J. S. Moon, H. I. Yoo, J. Y. Jung, M. S. Kim, J. T. Koh, W. J. Kim, and S. H. Kim. "Osteoprotegerin Expressed by Osteoclasts." Journal of Dental Research 93, no. 11 (September 25, 2014): 1116–23. http://dx.doi.org/10.1177/0022034514552677.
Full textAbstract:
Osteoprotegerin (OPG) is secreted by stromal and osteoblastic lineage cells and inhibits osteoclastogenesis by preventing the interaction of receptor activator of nuclear factor-κB ligand (RANKL) with receptor activator of nuclear factor-κB (RANK). In this study, the expression of OPG in osteoclasts themselves and its biological functions during osteoclastogenesis were investigated for the first time. OPG expression in vivo in the developing rat maxilla was examined by immunofluorescence analysis. OPG expression in osteoclasts during in vitro osteoclastogenesis was determined by reverse-transcription polymerase chain-reaction (RT-PCR), Western blot, and immunofluorescence staining. We determined the function of OPG produced by osteoclasts during osteoclastogenesis by silencing the OPG gene. The effects of OPG on bone-resorbing activity and apoptosis of mature osteoclasts were examined by the assay of resorptive pit formation on calcium-phosphate-coated plate and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, respectively. In the immunofluorescence findings, strong immunoreactivities were unexpectedly seen in multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts around the growing and erupting tooth germs in the rat alveolar bone. In vitro, OPG expression was significantly increased during the differentiation of osteoclasts from mouse bone-marrow-derived cells treated with a combination of macrophage colony-stimulating factor (M-CSF) and RANKL. Interestingly, it was found that OPG small interfering (si)RNA treatment during osteoclastogenesis enhanced the sizes of osteoclasts, but attenuated their bone-resorbing activity. Also, the increased chromosomal DNA fragmentation and caspase-3 activity in the late phase of osteoclastogenesis were found to be decreased by treatment with OPG siRNA. Furthermore, effects of OPG siRNA treatment on osteoclastogenesis and bone-resorbing activity were recovered by the treatment of exogenous OPG. These results suggest that OPG, expressed by the osteoclasts themselves, may play an auto-regulatory role in the late phase of osteoclastogenesis through the induction of apoptosis.
45
Castaman, Giancarlo, Daniela Melchiorre, and Silvia Linari. "Clinical, Instrumental, Serological and Histological Findings Suggest That Hemophilia B May be Less Severe Than Hemophilia A." Blood 126, no. 23 (December 3, 2015): 4682. http://dx.doi.org/10.1182/blood.v126.23.4682.4682.
Full textAbstract:
Abstract Background: Recent evidences suggest that patients with severe hemophilia B (HB) may have a less severe disease compared to severe hemophilia A (HA). Objectives: to investigate clinical, radiological, laboratory and histological differences in the arthropathy of severe HA and HB. Patients/Methods: 70 HA and 35 HB patients with at least one joint bleeding were consecutively enrolled. In all patients were assessed: joint bleedings (<10, 10-50, >50), regimen of treatment (prophylaxis/on demand), WFH, Pettersson and ultrasound (US) scores, serum sRANKL and OPG. Expression of RANK, RANKL and OPG was also evaluated in synovial tissue from 18 HA and 4 HB patients. Chi-square test, T-test, Mann-Whitney and Spearman's rank correlation coefficient were performed. Results: The percentage of patients with either 10-50 or >50 hemarthrosis was greater in HA than in HB (p< 0.001 and p = 0.03, respectively); that with <10 hemarthrosis was higher in HB (p < 0.0001). The mean value of WFH (36.6 vs 20.2;p <0.0001) and US scores (10.9 vs 4.3;p <0.0001) were significantly higher in HA patients. Serum OPG and s RANKL were decreased in HA versus HB (p<0.0001 and p=0.006, respectively) and also in HA patients with>50 hemarthrosis. The expression of OPG was markedly reduced in synovial tissue from HA patients. Conclusions: The reduced number of hemarthrosis, the lower WFH and US scores and higher OPG levels in serum and expression in synovial tissue in HB suggest that HB is a less severe disease than HA. OPG reduction seems to play a pivotal role in the progression of arthropathy in HA. Disclosures No relevant conflicts of interest to declare.
46
Rajakumar, Sujeetha A., Eniko Papp, Ildiko Grandal, Daniele Merico, Careesa C. Liu, Bedilu Allo, Lucia Zhang, et al. "RANK-RANKL Mediated Bone Destruction in B-Cell Acute Lymphoblastic Leukemia." Blood 128, no. 22 (December 2, 2016): 908. http://dx.doi.org/10.1182/blood.v128.22.908.908.
Full textAbstract:
Abstract Survival rates for pediatric B-Cell Acute Lymphoblastic Leukemia (B-ALL) have improved dramatically over the past 40 years approaching a current long-term survival rate of 85%. However childhood B-ALL patients continue to confront co-morbidities and their long-term consequences. For example, osteopenia and osteoporosis associated fractures are a common complication of pediatric leukemia at diagnosis, during treatment and in long-term B-ALL survivors. The STeroid-associated Osteoporosis in the Pediatric Population (STOPP) study reported that at ALL diagnosis, 16% of children and adolescents present with bone pain, vertebral compression and low vertebral Bone Mineral Density (BMD) scores, with the greatest incidence of vertebral fractures (VF) seen in the first year following diagnosis (J Clin Endocrinol Metab. 2015, 100:3408-17). Glucocorticoid treatment further elevated fracture risk in this population. These data underscore the need to identify molecular mechanism by which leukemic cells contribute to bone loss, and provide targeted therapies to limit these effects. Our laboratory previously showed that Rag2-/- p53-/- Prkdcscid/scid triple mutant (TM) and p53-/- Prkdcscid/scid double mutant (DM) mice develop spontaneous B-ALL, but only TM animals exhibit dissemination of leukemic blasts to the leptomeninges of the CNS, a poor prognosis feature observed in pediatric and adult ALL patients. We observed that TM leukemic mice also displayed fragile vertebral bones. Using comparative transcriptome analysis, we found that RANKL (Receptor Activator of the Nuclear factor-kB Ligand), a Tumor Necrosis Factor (TNF) superfamily member ligand and a key regulator of B cell and osteoclast differentiation, was expressed at greater levels in TM compared to the DM leukemia cells. RANKL binds to its receptor RANK, which is expressed in osteoclast precursor cells. RANK-RANKL interaction induces signaling in the osteoclast precursors and drives their differentiation into mature bone resorbing osteoclasts (Proc. Natl. Acad. Sci. 1999, 96:3540-3545). Upon adoptive leukemia cell transfer into immune deficient mice, RANKL+ TM but not DM cells caused decreased vertebral trabecular bone density in the recipients. Treatment with the recombinant RANKL antagonist protein Osteoprotegerin (OPG-Fc) inhibited the growth and dissemination of RANKL+TM leukemic cells and attenuated bone destruction in the recipient mice. These data suggested that TM mouse leukemia cells cause bone loss in the absence of glucocorticoid or other chemotherapy agents. We then examined the potential role of RANKL in osteoporosis associated with human B-ALL. RANKL mRNA was expressed by a majority of primary human adult and pediatric B-ALL. To determine whether primary patient B-ALL can cause bone loss, we transplanted RANKL+ human B-ALL samples of multiple cytogenetic high-risk subgroups (Complex, hypo-diploid and Mixed Lineage Leukemia (MLL) rearranged) into NOD.SCID.gC-/-(NSG) recipient mice. Micro-CT imaging and bone density measures in the xenotransplant recipients revealed extensive vertebral trabecular bone destruction. Immuno-histological analysis of the human B-ALL recipient mice demonstrated extensive osteoporotic damage of the long bones and marked RANKL protein expression in the long bones of mice harboring extensive human B-ALL cell burden compared to NSG control mice. To determine whether RANKL-RANK interaction was required for the B-ALL mediated bone destruction, cohorts of NSG mice engrafted with human B-ALL were treated with recombinant OPG-Fc compared to a matched Fc control protein. OPG-Fc treatment did not attenuate leukemia cell expansion and bone marrow burden, but despite bulky disease, the treatment conferred robust protection from bone destruction suggesting that RANKL was a critical mediator of this clinical complication. Our data demonstrate a central role of the RANK-RANKL axis in B-ALL-mediated bone disease and identify an actionable therapeutic target to reduce acute and long-term morbidity. Denosumab, an anti-RANKL antibody has been approved for the treatment of bone metastasis by solid tumors and for post-menopausal osteoporosis. Our pre-clinical studies suggest that Denosumab and other agents that inhibit the RANK-RANKL pathway may be efficacious in patients with B-ALL associated bone degeneration. Disclosures No relevant conflicts of interest to declare.
47
LI, XIAOMING, YAOMING LIU, BIN WU, ZHILONG DONG, YICHEN WANG, JIANZHONG LU, PING SHI, WENLONG BAI, and ZHIPING WANG. "Potential role of the OPG/RANK/RANKL axis in prostate cancer invasion and bone metastasis." Oncology Reports 32, no. 6 (September 23, 2014): 2605–11. http://dx.doi.org/10.3892/or.2014.3511.
Full text
48
Castaneda, B., and F. Lezot. "Second permanent molars: embryological origin, development and eruption. Role of the RANK/RANKL/OPG pathway." Journal of Dentofacial Anomalies and Orthodontics 18, no. 4 (2015): 402. http://dx.doi.org/10.1051/odfen/2015019.
Full text
49
Sagalovski, S. "OSTEOPOROSIS: CELLULAR AND MOLECULAR MECHANISMS OF DEVELOPMENT AND TARGET MOLECULES IN SEARCH FOR NEW TREATMENTS OF THE DISEASE." Osteoporosis and Bone Diseases 15, no. 1 (April 15, 2012): 15–22. http://dx.doi.org/10.14341/osteo2012115-22.
Full textAbstract:
In a review of the literature reflects the modern understanding of the cellular-molecular mechanism development of osteoporosis. Reflects the importance of cytokine RANKL-RANK-OPG sistem and Wnt/β-catenin signaling pathway in the development process of osteoblasto- and osteoclastogenesis. Noting the key role in the process of bone formation a number of molecules of cell signaling pathway and their antagonists are of interest as a target molecule to search for new drugs treatment for osteoporosis.
50
Litvynova, A., and L. Pasiieshvili. "Pathogenetic and diagnostic role of osteoprotegerin in the combined course of osteoarthritis and obesity." Journal of Education, Health and Sport 12, no. 5 (May 31, 2022): 284–91. http://dx.doi.org/10.12775/jehs.2022.12.05.022.
Full textAbstract:
In recent years, it has been proven that the formation of OA can occur against the background of impaired bone metabolism.
Bone remodeling is considered as a continuous complex process aimed at eliminating microdamages and updating the bone matrix. A key link in the regulation of this process is the system RANK / RANKL / OPG (osteoprotegerin), which provides a balance of activity of osteoblasts and osteoclasts. It blocks the interaction between RANK and RANKL by intercepting the RANKL ligand, which inhibits osteoclast development and reduces bone resorption.
Thus, these properties of OPG can be considered as one of the pathogenetic factors in patients with dystrophic joint lesions.
Objective: to investigate the content and role of osteoprotegerin in young patients with osteoarthritis, which occurs against the background of changes in body weight.
Materials and methods. The study involved 75 young patients (mean age - 30.92 ± 0.546 years) with overweight or obesity, who in the previous stages of the study was diagnosed with osteoarthritis (main group). The comparison group was represented by 50 patients with osteoarthritis and normal body weight. The age of patients was 30.95 ± 0.545 years; as in the previous group, men predominated - 64% and 36% respectively.
Benchmarks of osteoprotegerin were obtained in a study of 37 relatively healthy individuals of the same age and sex.
The level of osteoprotegerin was determined by enzyme-linked immunosorbent assay using the FineTest EH0247 reagent kit, China.
The outcomes were processed by the methods of variation statistics using the computer program STATISTICA.Results and discussion. When determining the content of OPG in the serum of patients of the main group was found to increase to 124.03 pg / ml, against control - 65.64 pg / ml. In the group of patients with isolated OA, this value was 92.29 pg / ml. Meaning that, in OA, running on the background of altered BMI, the content of OPG is likely to increase, both in relation to the norm and the results of the comparison group (p <0,001).
The formation and course of osteoarthritis is accompanied by an increase in osteoprotegerin, the content of which depends on the degree of obesity and the radiological stage of the process.
Conclusions: The course of osteoarthritis is accompanied by an increase in osteoprotegerin, which is considered a negative regulator of bone resorption.
In osteoarthritis, which occurs against the background of changes in body mass index, a direct correlation with the degree of obesity.
Changes in osteoprotegerin in patients with osteoarthritis depend on the radiological stage of joint damage and are most pronounced in individuals with stage 2 obesity and stage 2 radiological changes