To elucidate the mechanism involved in the oxidized lipid-induced RANKL production in T lymphocytes, we tested a panel of pathway inhibitors, using concentrations that did not affect cell viability. We first investigated the NFκB pathway, based on previous reports showing that this pathway is central to the maturation and activation of osteoclast precursor cells induced by RANK/RANKL binding [44]. Furthermore, the biological activity of MM-LDL and oxidized lipids in several other cell types is mediated, at least in part, through the NFκB pathway [49]. Two different NFκB inhibitors were used, one that blocks the translocation of the active NFκB complex from the cytoplasm into the nucleus (inhibitor 1), and one that prevents the phosphorylation of IκBα (inhibitor 2). We found that the MM-LDL-induced RANKL production by the stimulated T lymphocytes was only modestly reduced when the NFκB pathway was inhibited. (Fig. 3A). By contrast, in the unstimulated T lymphocytes, RANKL production ...
TY - JOUR. T1 - Novel inhibitors of RANKL-induced osteoclastogenesis. T2 - Design, synthesis, and biological evaluation of 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones. AU - Lee, Chia Chung. AU - Liu, Fei Lan. AU - Chen, Chun Liang. AU - Chen, Tsung Chih. AU - Liu, Feng Cheng. AU - Ahmed Ali, Ahmed Atef. AU - Chang, Deh Ming. AU - Huang, Hsu Shan. PY - 2015/7/23. Y1 - 2015/7/23. N2 - A series of novel 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivatives were synthesized and evaluated for their inhibitory effects on osteoclast activities by using TRAP-staining assay. Among the tested compounds, 3d and 3h exhibited more potent osteoclast-inhibitory activities than the lead compound NDMC503 (a ring-fused structure of NDMC101), as reported in our previous study. Both 3d and 3h exhibited two-fold increase in activity compared to NDMC503. In addition, our biological results indicated that 3d and 3h could suppress RANKL-induced ...
Identification of Nedd9 as a TGF-β-Smad2-3 Target Gene Involved in RANKL-Induced Osteoclastogenesis by Comprehensive Analysis. . Biblioteca virtual para leer y descargar libros, documentos, trabajos y tesis universitarias en PDF. Material universiario, documentación y tareas realizadas por universitarios en nuestra biblioteca. Para descargar gratis y para leer online.
Vitamin D3, and its most active form 1,25(OH)2D3, are well known to stimulate osteoclastogenesis through stromal cell induction of the receptor activator of nuclear factor kappaB ligand (RANKL). Mitogen activating protein kinase phosphatase-1 (MKP-1) is a phosphatase classically known to negatively regulate the immune response through dephosphorylation of p38, ERK, and JNK activity. Objective: The purpose of this study was to define the role of MKP-1 in genomic 1,25(OH)2D3 signaling and downstream osteoclastogenesis through RANKL. Methods: Primary bone marrow stromal cells (BMSCs) from tibias and femurs of MKP-1-/- and MKP-1+/+ mice were collected. Gene expression was measured using RT-qPCR, protein expression by immunoblot and ELISA in 1,25(OH)2D3 treated cultures. Co-culture osteoclastogenesis assays were conducted as well. Results: RT-qPCR and immunoblot analysis comparing BMSCs revealed that 1,25(OH)2D3-induced VDR, CYP24a1 and RANKL mRNA expression and protein were significantly attenuated ...
The importance of RankL as a key osteoclastogenic factor in bone remodeling is now well established (63). Perhaps most persuasive is the finding through deletion studies in mice that the loss of either RankL or its receptor (Rank) results in a significant deficiency in osteoclast production (20, 37). Indeed, several osteoporotic states in humans have been ascribed to genetic defects in the RANKL/RANK/OPG signaling pathway (68). Thus, although factors separate from RankL are known to play roles in the osteoclastogenic process (35, 63), it is clear that this gene product and its signal transduction pathway are key components. An understanding of the mechanisms whereby this gene is regulated is therefore of paramount importance.. Our studies using ChIP/chip analysis, direct ChIP, and more traditional molecular approaches identified five distinct regions located at significant distances upstream of the TSS that were responsible for regulating the expression of the RankL gene. VDR and RXR localize to ...
Receptor activator of NF-kappaB ligand (RANKL), its signaling receptor RANK, and its decoy receptor osteoprotegerin (OPG) constitute a molecular triad that is critical in regulating bone remodeling, and also plays multiple roles in the immune system. OPG binds RANKL directly to block its interaction with RANK. In this article, we report the 2.7-A crystal structure of human RANKL trimer in complex with the N-terminal fragment of human OPG containing four cysteine-rich TNFR homologous domains (OPG-CRD). The structure shows that RANKL trimer uses three equivalent grooves between two neighboring monomers to interact with three OPG-CRD monomers symmetrically. A loop from the CRD3 domain of OPG-CRD inserts into the shallow groove of RANKL, providing the major binding determinant that is further confirmed by affinity measurement and osteoclast differentiation assay. These results, together with a previously reported mouse RANKL/RANK complex structure, reveal that OPG exerts its decoy receptor function ...
Principal Investigator:KITAZAWA Riko, Project Period (FY):2002 - 2003, Research Category:Grant-in-Aid for Scientific Research (C), Section:一般, Research Field:Experimental pathology
Context: Prostate cancer (PCa) cells are characterised by an exquisite tropism for the bone, which translates into one of the highest rates of bone metastases and skeletal morbidity. New, effective treatments have emerged from a better understanding of the physiopathology of bone metastases. Objective: To summarise current insights and future perspectives in the therapy of PCa-induced bone disease. Evidence acquisition: This manuscript is based on presentations given at a satellite symposium held at the 2nd World Congress on Controversies in Urology (CURy) in Lisbon, Portugal. Data were retrieved from original and recent review papers on PCa-induced bone disease. Evidence synthesis: In normal, healthy bone, there is a balance between bone resorption and bone formation through the coordinated activity of osteoclasts and osteoblasts. The receptor activator of nuclear factor-kappa B ligand (RANKL) is an essential mediator of osteoclast formation, function, and survival. The RANKL pathway represents ...
Sigma-Aldrich offers abstracts and full-text articles by [Gary J Spencer, Jennifer C Utting, Sharon L Etheridge, Timothy R Arnett, Paul G Genever].
Rabbit polyclonal RANKL antibody validated for WB, ELISA, IHC, ICC/IF and tested in Human. Referenced in 12 publications and 4 independent reviews.
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TY - JOUR. T1 - Eriodictyol Inhibits RANKL-Induced Osteoclast Formation and Function Via Inhibition of NFATc1 Activity. AU - Song, Fangming. AU - Zhou, Lin. AU - Zhao, J.. AU - Liu, Q.. AU - Yang, Mingli. AU - Tan, R.. AU - Xu, J.. AU - Zhang, G.. AU - Quinn, J.M.W.. AU - Tickner, Jennifer. AU - Huang, Y.. AU - Xu, Jiake. PY - 2016/9. Y1 - 2016/9. N2 - © 2016 Wiley Periodicals, Inc. Receptor activator of nuclear factor kappa-B ligand (RANKL) induces differentiation and function of osteoclasts through triggering multiple signaling cascades, including NF-?B, MAPK, and Ca2+-dependent signals, which induce and activate critical transcription factor NFATc1. Targeting these signaling cascades may serve as an effective therapy against osteoclast-related diseases. Here, by screening a panel of natural plant extracts with known anti-inflammatory, anti-tumor, or anti-oxidant properties for possible anti-osteoclastogenic activities we identified Eriodictyol. This flavanone potently suppressed ...
Full Text - Excessive alcohol consumption is positively related to osteoporosis, and its treatment strategies are poorly developed. Disulfiram inhibits receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis; however, whether it can be used for ethanol-induced osteoclastogenesis and its underlying mechanism are still unclear. In this study, we demonstrated that ethanol promoted RANKL-induced osteoclast formation and bone resorption, whereas, disulfiram suppressed ethanol-induced osteoclastogenesis by abrogating the expression of nuclear factor of activated T cell c1 (NFATc1) in vitro. Further analysis revealed that aldehyde dehydrogenase 1A1 (ALDH1A1) is important for the expression of NFATc1, the master regulator of osteoclast differentiation. Furthermore, we showed that disulfiram protected ethanol-induced osteoporosis in vivo. Overall, our study provides promising evidence that disulfiram can be used as a treatment strategy for alcohol-related osteoporosis via the
The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption. Osteob... more
Receptor activator of nuclear factor kappa-Β ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene. RANKL is known as a type II membrane protein and is a member of the tumor necrosis factor (TNF) superfamily. RANKL has been identified to affect the immune system and control bone regeneration and remodeling. RANKL is an apoptosis regulator gene, a binding partner of osteoprotegerin (OPG), a ligand for the receptor RANK and controls cell proliferation by modifying protein levels of Id4, Id2 and cyclin D1. RANKL is expressed in several tissues and organs including: skeletal muscle, thymus, liver, colon, small intestine, adrenal gland, osteoblast, mammary gland epithelial cells, prostate and pancreas. Variation in concentration levels of RANKL throughout several organs, reconfirm ...
IL-1 is a proinflammatory cytokine that acts as an important mediator of the peripheral immune response during infection and inflammation (33). It is also known that IL-1 can induce bone destruction in a variety of diseases such as osteoporosis, rheumatoid arthritis, and periodontal disease (34, 35). IL-1 stimulates osteoclast differentiation, fusion, and activation (35). In this paper, we examined the direct effect of IL-1 on osteoclast precursors which led to the elucidation of a previously unknown mechanism of downstream signaling pathways during IL-1-induced osteoclastogenesis.. Although TNF-α and IL-1 can activate early signaling pathways including NF-κB, JNK, and p38, which are important for RANKL-induced osteoclast differentiation, TNF-α alone has been shown to induce osteoclast differentiation in vitro (21, 36). IL-1 activates mature osteoclasts, thereby enhancing bone resorption (35), but our data along with previous studies (35, 36) demonstrate that IL-1 alone is insufficient to ...
Based on our earlier observation that caspase-3 is present in osteoclasts that are not undergoing apoptosis, we investigated the role of this protein in the differentiation of primary osteoclasts and RAW264.7 cells (Szymczyk KH, et al, 2005, Caspase-3 activity is necessary for RANKL-induced osteoclast differentiation. The Proceedings of the 8th ICCBMT). We noted that osteoclast numbers are decreased in long bones of procaspase-3 knockout mice and that receptor activator of NF-κB ligand (RANKL) does not promote differentiation of isolated preosteoclasts. In addition, after treatment with inhibitors of caspase-3 activity, neither the wild-type primary nor the RAW264.7 cells express TRAP or became multinucleated. We found that immediately following RANKL treatment, procaspase-3 is cleaved and the activated protein is localized to lipid regions of the plasma membrane and the cytosol. We developed RAW264.7 procaspase-3 knockdown clonal cell lines using RNAi technology. Again, treatment with RANKL fails to
in Clinical & Experimental Immunology (2004), 138(3), 491-498. Crohns disease (CD) is associated with low bone mass due to chronic inflammation and other factors. Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor ... [more ▼]. Crohns disease (CD) is associated with low bone mass due to chronic inflammation and other factors. Receptor activator of NF-kappaB ligand (RANKL), its receptor RANK and its decoy receptor osteoprotegerin (OPG) are potentially involved in this process as they regulate osteoclastogenesis and are influenced by pro-inflammatory cytokines. The aim of this study was to determine the levels of soluble RANKL (sRANKL), RANK and OPG expression both in the serum and in the colon of CD patients. Levels of sRANKL and OPG were assessed in the serum and the supernatants of cultured colonic biopsies in patients with CD and controls by ELISA. RANK expression was explored by immunostaining and immunofluorescence of fixed colonic samples. OPG and ...
Methods Bone marrow cells (BMCs) were obtained from 5-week-old male ICR mice and cultured to be differentiated into osteoclasts with M-CSF and RANKL in the presence or absence of IL-1β, TG, or TAC. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining and resorption pit assay with dentine slice. The molecular mechanisms of the above effects of TAC on osteoclastogenesis were investigated by using RT-PCR and immunoblotting for osteoclast specific and ER stress signaling molecules, including PERK, IRE1, GRP78, eIF2α, c-Fos and NFATc1.. ...
Transforming growth factor beta (TGFbeta) is a multifunctional growth factor that is produced by many cells in bone and is abundant in the bone matrix. TGFbeta is known to regulate RANKL-induced osteoclast formation and bone resorbing activity. In this study we sought to determine whether TGFbeta could directly induce osteoclast formation by a RANKL-independent mechanism. We found that the addition of TGFbeta to cultures of human monocytes and RAW 264.7 cells (in the presence of M-CSF and the absence of RANKL, TNFalpha or IL-6/IL-11) was sufficient to induce the formation of TRAP+ and VNR+ cells, which formed actin rings and were capable of extensive lacunar resorption. The addition of osteoprotegerin or antibodies to TNFalpha and its receptors, as well as antibodies to gp130, did not inhibit lacunar resorption, indicating that TGFbeta did not act by stimulating RANKL, TNF or IL-6 production by monocytes. TGFbeta-induced osteoclast formation was qualitatively different from that induced by RANKL with
TY - JOUR. T1 - Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma. AU - Kim, Hyun Soo. AU - Yoon, Gun. AU - Do, Sung Im. AU - Kim, Sung Joo. AU - Kim, Youn Wha. PY - 2016/3/22. Y1 - 2016/3/22. N2 - A better understanding of tumor biology is important in the identification of molecules that are down-regulated in malignancy and in determining their role in tumor suppression. The aim of this study was to analyze osteoprotegerin (OPG) expression in colorectal carcinoma (CRC) and to investigate the underlying mechanism for changes in the expression of OPG. OPG expression was assessed in CRC tissue samples and cell lines. The methylation status of the OPG promoter region was determined, and the effects of demethylation on OPG expression were analyzed. The effects of recombinant OPG (rOPG) administration on cellular functions were also investigated. Clinical and prognostic implications of OPG protein expression in CRC patients were analyzed. The CRC tissues and ...
A new inhibitor, placotylene A (1), of the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation, and a regioisomer of placotylene A, placotylene B (2), were isolated from a Korean marine sponge Placospongia sp. The chemical structures of placotylenes A and B were elucidated on the basis of 1D and 2D NMR, along with MS spectral analysis and revealed as an iodinated polyacetylene class of natural products. Placotylene A (1) displayed inhibitory activity against RANKL-induced osteoclast differentiation at 10 μM while placotylene B (2) did not show any significant activity up to 100 μM, respectively.
A small peptide, OP3-4, blocks receptor activator of NF-κB from binding to its ligand, receptor activator of NF-κB ligand (RANKL), and was reported recently to inhibit bone resorption, promote bone formation and protect cartilage in a preclinical rheumatoid arthritis model. The latter effects may result from inhibition of RANKL reverse signalling in osteoblasts and chondrocytes. Whether other RANKL inhibitors, such as denosumab, share this action is not known, but OP3-4 at least has potential to provide anabolic treatment for both systemic and focal bone loss in inflammatory arthritis.
Recent works demonstrated the difference of calcification genesis between carotid and femoral plaques, femoral plaques being more calcified. It has been clearly demonstrated that the molecular triad osteoprotegerin (OPG)/Receptor Activator of NFkB (RANK)/RANK Ligand (RANKL) exerts its activities in the osteoimmunology and vascular system. The aim of this study was to determine their expression and their potential role in calcifications of the atheromatous plaques located in two different peripheral arterial beds, carotid and femoral. The expression of OPG, RANK and RANKL was analyzed by immunochemistry in 40 carotid and femoral samples. Blood OPG and RANKL were quantified using specific ELISA assays. OPG staining was more frequently observed in carotid than in femoral plaques, especially in lipid core. Its expression correlated with macrophage infiltration more abundantly observed in carotid specimens. Surprisingly, serum OPG concentration was significantly lower in carotid population compared to
BACKGROUND: Interleukin-32 (IL-32) is a newly described cytokine produced after stimulation by IL-2 or IL-18 and IFN-gamma. IL-32 has the typical properties of a pro-inflammatory mediator and although its role in rheumatoid arthritis has been recently reported its effect on the osteoclastogenesis process remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we have shown that IL-32 was a potent modulator of osteoclastogenesis in vitro, whereby it promoted the differentiation of osteoclast precursors into TRAcP+ VNR+ multinucleated cells expressing specific osteoclast markers (up-regulation of NFATc1, OSCAR, Cathepsin K), but it was incapable of inducing the maturation of these multinucleated cells into bone-resorbing cells. The lack of bone resorption in IL-32-treated cultures could in part be explain by the lack of F-actin ring formation by the multinucleated cells generated. Moreover, when IL-32 was added to PBMC cultures maintained with soluble RANKL, although the number of newly
2924 Genrally, prostatic cancer shows osteoblastic metastases, whereas the lesion also causes osteolysis. The present study was undertaken to test the effects of prostate cancer cell lines (LNCaP, DU145, PC3, and MDA PCa 2b) on osteoclastogenesis. Using a reverse transcription-polymerase chain reaction approach, we investigated the effects of crude conditioned medium (CM) obtained from prostate cancer cell lines on mRNA level of receptor activator of NF-κB ligand (RANKL) and its decoy receptor, osteoprotegerin (OPG) in mouse osteoblastic cell line, MC3T3-E1. Then we cocultured MC3T3-E1 with prostate cancer cell lines and evaluated mRNA level of RANKL and OPG in MC3T3-E1. Next, to investigate the effects on osteoclast precursor generated from mouse bone marrow treated with RANKL and MCSF, we cultured osteoclast precursor with crude CM obtained from prostate cancer cell lines in the presence or absence of RANKL or OPG. The number of multinucleated osteoclasts was evaluated by TRAP staining. Crude ...
The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB-induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro ...
With the increasing age of people living with HIV/AIDS, age-induced osteoporosis is likely to be compounded by HIV/AIDS and HAART-associated bone loss. Mechanistically, osteoclasts the cells responsible for bone resorption form under the influence of the key osteoclastogenic cytokine Receptor- Activator of NF-KB (RANKL). The osteoclastogenic and proresorptive activities of RANKL are moderated by its physiological decoy receptor osteoprotegerin (OPG). Imbalance in the ratio of RANKL to OPG alters osteoclastic bone resorption and lead to osteoporosis. Activated T- and B-cells are a major source of RANKL, while normal physiological B-cells are a major source of OPG. T-cells regulate the production of OPG by B-cells. Thus changes in the immune system induced by HIV/AIDS and/or by HAART could affect B-cell and T-cells RANKL and OPG production. Indeed, data from our group shows that in an animal model of HIV/AIDS, the HIV-1 Transgenic rat, the development of osteoporosis is recapitulated as observed ...
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beta(3) integrin-null osteoclasts are dysfunctional, but their numbers are increased in vivo. In vitro, however, the number of beta(3)(-/-) osteoclasts is reduced because of arrested differentiation. This paradox suggests cytokine regulation of beta(3)(-/-) osteoclastogenesis differs in vitro and in vivo. In vitro, additional MCSF, but not receptor activator of NF-kappaB ligand (RANKL), completely rescues beta(3)(-/-) osteoclastogenesis. Similarly, activation of extracellular signal-regulated kinases (ERKs) and expression of c-Fos, both essential for osteoclastogenesis, are attenuated in beta(3)(-/-) preosteoclasts, but completely restored by additional MCSF. In fact, circulating and bone marrow cell membrane-bound MCSFs are enhanced in beta(3)(-/-) mice, correlating with the increase in the osteoclast number. To identify components of the MCSF receptor that is critical for osteoclastogenesis in beta(3)(-/-) cells, we retrovirally transduced authentic osteoclast precursors with chimeric c-Fms constructs
Summary: Rapid progress has been made in recent years in our understanding of the mechanisms regulating the formation, activation, and survival of osteoclasts, which are derived from precursor cells in the myeloid lineage. In contrast, study of the regulation of osteoclast precursors (OCPs) has been relatively slow, in part because it has been hard to accurately identify them. However, following the discovery of cell-surface markers that facilitated purification of OCPs, recent studies have demonstrated that peripheral blood OCP numbers are increased in tumor necrosis factor (TNF)-mediated arthritis, both in animals and humans, and these numbers correlate with serum TNF levels. The increase can be reversed by anti-TNF therapy. Furthermore, the precursor cells that give rise to osteoclasts can also differentiate into other cell types, including dendritic cells. Receptor activator nuclear factor-κB ligand (RANKL) stimulates OCPs to produce pro-inflammatory cytokines and chemokines, and RANKL ...
Receptor activator of NF-κB ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. A neutralizing Ab against RANKL, denosumab, improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchennes muscular dystrophy (mdx) and denervation-induced atrophy, but its role and mechanisms of action on muscle weakness in other conditions remain to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKLTg+), or lack Pparb and concomitantly develop sarcopenia (Pparb-/-). In women, taking denosumab for more than 3 years improved appendicular lean mass and handgrip strength compared with no treatment, whereas bisphosphonate did not. HuRANKLTg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in ...
353 Serum osteoprotegerin/osteoclastogenesis-inhibitory factor during pregnancy and lactation and the relationship with calciumregulating hormones and bone turnover markers H Uemura, T Yasui, M Kiyokawa, A Kuwahara, H Ikawa, T Matsuzaki, M Maegawa, H Furumoto and M Irahara Department of Obstetrics and Gynecology, University of Tokushima, School of Medicine, 3-18-15, Kuramoto-cho, Tokushima 770-8503, Japan (Requests for offprints should be addressed to H Uemura; Email: [email protected]) Abstract Pregnancy and lactation induce dynamic changes in maternal bone and calcium metabolism. A novel cytokine termed osteoprotegerin (OPG)/osteoclastogenesisinhibitory factor (OCIF) was recently isolated; this cytokine inhibits osteoclast maturation. To define the effects of pregnancy and lactation on circulating OPG/OCIF in mothers, we studied the changes in the levels of OPG/ OCIF as well as those of calcium-regulating hormones and biochemical markers of bone turnover in the maternal circulation during ...
Receptor Activator of NF-?B Ligand (RANKL) is a cell-bound marker (CD254) related to the TNF family of proteins. RANKL plays a critical role in bone metabolism, particularly osteoclast differentiation. In addition, RANKL is expressed by some T cells and i
Breast cancer is the most common cancer among women, affecting one in eight women, and is the second leading cause of mortality from cancer. Bone metastases are a frequent complication of breast cancer, and the mechanism of breast cancer metastases to bone is an ongoing area of research.. Receptor activator of NF-kB (RANK) and its ligand (RANKL) have been identified and characterized for its role in bone remodeling. RANKL is a member of the tumor necrosis factor (TNF) family of cytokines that binds to its receptor RANK to control osteoclast differentiation, activation, and survival. RANK protein expression is not only found on osteoclasts and dendritic cells but also on T cells and mammary epithelial cells. RANK and RANKL is important for lymph node and thymus formation as well as lactating mammary gland development during pregnancy. Furthermore, the RANK/RANKL axis has been linked to progestin driven breast carcinomas and bone metastases.. RANK is expressed in 6-57% of invasive human breast ...
Background In treating rheumatoid arthritis (RA), T2T (treat-to-Target) is the most reliable treatment strategy. Recent reports have indicated that reaching normal levels of bone mineral density (BMD) might be important for the prevention of fractures in osteoporosis treatment (reference 1 and 2).From this fact, there might be a possibility that T2T targeting BMD might be feasible also in osteoporosis treatment. In doing so, medicines with the ability to sufficiently increase BMD at a fast speed should be needed. Denosumab (DMAb) specifically inhibits the receptor activator for nuclear factor-kappa B ligand (RANKL) improves BMD rapidly at lumbar or hip. Therefore, DMAb is one of candidate drugs for T2T practice, and it is very important to know risk factors that attenuate its effect in the treatment of osteoporosis. ...
Osteoclasts, the only cells with bone tissue resorption functions through the usage of prostheses can inevitably result in the era of wear contaminants, the effective inhibition of osteoclast development, and bone tissue resorption could be a good way to avoid the loosening of prostheses and for that reason extend their lives. precursor cells in localized lesions in Varespladib RA. The overexpression of RANKL by energetic lymphocytes, macrophages, osteoblasts, etc. qualified prospects to extreme proliferation and irregular activation of osteoclasts due to the binding of RANKL to RANK on the top of osteoclast precursor cells and mature osteoclasts. As well as the overexpression of RANKL in broken joint bone tissue tissue, mRNA can be indicated by fibroblasts in the synovial cells, which leads towards the production from the RANKL proteins (36). Kotake et al. isolated multinucleated cells through the synovial lesions of RA individuals and demonstrated that they can form bone tissue absorption ...
TRAIL induced osteoclast differentiation is dependent on TRAF6.(A) Human peripheral blood mononuclear cells (PBMCs) were plated in 96-well plates at 1.5 × 105
Bone Metastasis-Free Survival. The median follow-up was 67.2 months in the denosumab group and 67.3 months in the placebo group. Median bone metastasis-free survival was not reached in either group (hazard ratio [HR] = 0.97, 95% confidence interval [CI] = 0.82-1.14, P = .70). Bone metastasis-free survival events occurred in 13% of the denosumab group vs 14% of the placebo group, including bone events in 7% vs 8%. Median disease-free survival was not reached in either group (HR = 1.04, P = .57). Disease-free survival events occurred in 20% vs 19% of patients.. Adverse Events. The most common grade ≥ 3 adverse events were neutropenia (15% vs 15%), febrile neutropenia (5% vs 6%), and leukopenia (3% vs 3%). Positively adjudicated osteonecrosis of the jaw occurred in 5% vs , 1% of patients. Atypical femur fracture occurred in nine patients (, 1%) vs no patients. Hypocalcemia of any grade occurred in 7% vs 4%.. The investigators concluded, "Despite preclinical evidence suggesting RANKL inhibition ...
Osteoclasts;Estrogen;Postmenopause;Bone and Bones;Bone Remodeling;RANK Ligand;Carrier Proteins;Mutation;Osteoporosis, Postmenopausal;Osteoprotegerin;Glycoproteins;Receptor Activator of Nuclear Factor-kappa B;Receptors, Cytoplasmic and ...
Abcams Osteoprotegerin ELISA Kit suitable for Cell culture supernatant, Serum, Plasma, Cell Lysate in human. Reliably quantify 1 pg/ml of Osteoprotegerin.
In the current study, we have generated a faithful computational model of the BMU. It is important to note that the homeostatic behavior is not hardcoded but emerges from the interactions between the different primary cell types of the bone in response to TGF-β, RANKL, and BDFs. Furthermore, informed by experimental evidence, the introduction of a simulated TGF-β ligand and receptor expressing prostate cancer cell into the BMU resulted in a vicious cycle that yielded mixed osteogenic/osteolytic lesions over clinically relevant periods of time. Key findings arising from the computational model include: (i) the ability to assess temporal changes in cellular populations and dissect complex dynamics that are difficult to determine in vivo, (ii) the phasic osteolytic/osteogenic nature of the metastases, (iii) the application of clinically used therapies such as bisphosphonates and anti-RANKL therapies illustrate the usefulness of the model in predicting the efficacy of targeted inhibitors, and (iv) ...
Receptor activator of NF-?B ligand (RANKL) is a TNF?-type cytokine that is produced by mesenchymal lineage cells such as chondrocytes, osteoblasts and osteocyte...
Use of an anti-IL-20 antibody, either alone or in combination with an anti-RANKL antibody, for treating breast cancer and inhibiting cancer-associated bone loss.
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Apoptosis, or programmed cell death, is a normal component of cellular differentiation and the development of multicellular organisms. Receptor activator ofNF-kB (RANK) lacks significant homology with the other family members of the tumor necrosis factor
Treatment with denosumab 60 mg and 180 mg (with background methotrexate) reduces the progression of bone erosion according to results of a 227 patient Phase II trial presented at EULAR 2007, the Annual European Congress of Rheumatology in Barcelona, Spain.
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