scholarly journals Zoledronate Enhances Osteocyte-Mediated Osteoclast Differentiation by IL-6/RANKL Axis

2019 ◽  
Vol 20 (6) ◽  
pp. 1467 ◽  
Author(s):  
Hyung Joon Kim ◽  
Ha Jin Kim ◽  
YunJeong Choi ◽  
Moon-Kyoung Bae ◽  
Dae Seok Hwang ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Clinical Importance ◽  
Osteonecrosis Of The Jaw ◽  
Severe Side Effect ◽  
Signal Transducer ◽  
Rankl Expression ◽  
Receptor Activator ◽  
Subsequent Activation ◽  
Transcription 3 ◽  
Nuclear Factor Kb

Bisphosphonates are one of the most widely used synthetic pyrophosphate analogues for the treatment of bone resorbing diseases such as osteoporosis, multiple myeloma, and bone metastases. Although the therapeutic usefulness of bisphosphonates mainly depends on their anti-osteoclastogenic effect, a severe side-effect of bisphosphonates called bisphosphonate-related osteonecrosis of the jaw (BRONJ) could not be explained by the anti-osteoclastogenic effect of bisphosphonates. In the present study, we have evaluated the changes in osteoclastogenesis- or osteoblastogenesis-supporting activities of osteocytes induced by bisphosphonates. Zoledronate, a nitrogen-containing bisphosphonate, markedly increased both the receptor activator of nuclear factor kB ligand (RANKL) as well as sclerostin in osteocyte-like MLO-Y4 cells, which were functionally revalidated by osteoclast/osteoblast generating activities of the conditioned medium obtained from zoledronate-treated MLO-Y4 cells. Of note, the zoledronate treatment-induced upregulation of the RANKL expression was mediated by autocrine interleukin-6 (IL-6) and subsequent activation of the signal transducer and activator of transcription 3 (STAT3) pathway. These results were evidenced by the blunted RANKL expression in the presence of a Janus activated kinase (JAK2)/STAT3 inhibitor, AG490. Also, the osteoclastogenesis-supporting activity was significantly decreased in zoledronate-treated MLO-Y4 cells in the presence of IL-6 neutralizing IgG compared to that of the control IgG. Thus, our results show previously unanticipated effects of anti-bone resorptive bisphosphonate and suggest a potential clinical importance of osteocytes in BRONJ development.

The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

2018 ◽  
Vol 69 (9) ◽  
pp. 2541-2545
Author(s):  
Raluca Barzoi ◽  
Elena Rezus ◽  
Codruta Badescu ◽  
Razan Al Namat ◽  
Manuela Ciocoiu
Keyword(s):  
Rheumatoid Arthritis ◽  
Immune Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Nuclear Factor ◽  
Receptor Activator ◽  
Level Function ◽  
Rheumatoid Polyarthritis ◽  
The Impact ◽  
Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

scholarly journals Interleukin-6 Inhibits Receptor Activator of Nuclear Factor κB Ligand-Induced Osteoclastogenesis by Diverting Cells into the Macrophage Lineage: Key Role of Serine727 Phosphorylation of Signal Transducer and Activator of Transcription 3

Endocrinology ◽  
2008 ◽  
Vol 149 (7) ◽  
pp. 3688-3697 ◽  
Author(s):  
Laurence Duplomb ◽  
Marc Baud’huin ◽  
Céline Charrier ◽  
Martine Berreur ◽  
Valérie Trichet ◽  
...  
Keyword(s):  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Signal Transducer ◽  
Blood Monocytes ◽  
Receptor Activator ◽  
Few Data ◽  
Macrophage Lineage

Osteoclasts are bone-resorptive cells that differentiate from hematopoietic precursors upon receptor activator of nuclear factor κB ligand (RANKL) activation. Previous studies demonstrated that IL-6 indirectly stimulates osteoclastogenesis through the production of RANKL by osteoblasts. However, few data described the direct effect of IL-6 on osteoclasts. To investigate this effect, we used several models: murine RAW264.7 cells, mouse bone marrow, and human blood monocytes. In the three models used, the addition of IL-6 inhibited RANKL-induced osteoclastogenesis. Furthermore, IL-6 decreased the expression of osteoclast markers and up-modulated macrophage markers. To elucidate this inhibition, signal transducer and activator of transcription (STAT) 3, the main signaling molecule activated by IL-6, was analyzed. Addition of two STAT3 inhibitors completely abolished RANKL-induced osteoclastogenesis, revealing a key role of STAT3. We demonstrated that a basal level of phosphorylated-STAT3 on Serine727 associated with an absence of phosphorylation on Tyrosine705 is essential for osteoclastogenesis. Furthermore, a decrease of Serine727 phosphorylation led to an inhibition of osteoclast differentiation, whereas an increase of Tyrosine705 phosphorylation upon IL-6 stimulation led to the formation of macrophages instead of osteoclasts. In conclusion, we showed for the first time that IL-6 inhibits RANKL-induced osteoclastogenesis by diverting cells into the macrophage lineage, and demonstrated the functional role of activated-STAT3 and its form of phosphorylation in the control of osteoclastogenesis.

scholarly journals Triiodothyronine (T3) does not induce Rankl expression in rat Ros 17/2.8 cells

2008 ◽  
Vol 52 (1) ◽  
pp. 109-113 ◽  
Author(s):  
Patrícia P. Saraiva ◽  
Silvania S. Teixeira ◽  
Célia Regina Nogueira ◽  
Carlos Roberto Padovani
Keyword(s):  
Messenger Rna ◽  
Nuclear Factor Kappa B ◽  
Osteoclast Differentiation ◽  
Hormone Treatment ◽  
Nuclear Factor ◽  
Rankl Expression ◽  
Loss Mechanism ◽  
Nuclear Factor Kappa ◽  
Rankl Mrna ◽  
Receptor Activator

Osteoclastogenesis may be regulated via activation of the RANK/RANKL (receptor activator of nuclear factor-kappa B/ receptor activator of nuclear factor-kappa B ligand) system, which is mediated by osteoblasts. However, the bone loss mechanism induced by T3 (triiodothyronine) is still controversial. In this study, osteoblastic lineage rat cells (ROS 17/2.8) were treated with T3 (10-8 M, 10-9 M, and 10-10 M), and RANKL mRNA (messenger RNA) expression was measured by semiquantitative RT-PCR. Our results show that T3 concentrations used did not significantly enhance RANKL expression compared to controls without hormone treatment. This data suggests that other mechanisms, unrelated to the RANK/RANKL system, might be to activate osteoclast differentiation in these cells.

scholarly journals Carbon Monoxide Inhibits Receptor Activator of NF-κB (RANKL)-Induced Osteoclastogenesis

2015 ◽  
Vol 36 (3) ◽  
pp. 1250-1258 ◽  
Author(s):  
Feng-Jen Tseng ◽  
Wei-Tso Chia ◽  
Chih-Hung Wang ◽  
Jia-Fwu Shyu ◽  
Guo-Hau Gou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Carbon Monoxide ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Rankl Expression ◽  
Arthritis Model ◽  
Ppar Γ ◽  
Pparγ Agonist ◽  
Receptor Activator

Background: Low concentrations of carbon monoxide (CO) have anti-inflammatory effects and can reduce bone erosion in a murine collagen-induced arthritis model. The objective of this study was to assess the effects of CO on receptor activator of NF-γB ligand (RANKL), one of the key stimulators of osteoclastogenesis. Methods: The in vivo effects of CO on RANKL expression were assessed in a collagen antibody-induced arthritis model in mice. Cell proliferation and apoptosis were assessed in the RAW246.7 cell line stimulated with RANKL and exposed to either air or CO. The number of tartrate resistant acid phosphatase (TRAP)-positive RAW246.7 cells was also examined after treatment with RANKL and the peroxisome proliferator-activated receptor gamma (PPARγ) agonist, Troglitazone. Results: CO reduced RANKL expression in the synovium of arthritic mice. Although CO slightly increased RAW246.7 cell proliferation, no differences in activated caspase 3 levels were detected. In addition, Troglitazone ameliorated the inhibitory effects of CO on RANKL-induced TRAP expression by RAW246.7 cells. Conclusions: CO suppresses osteoclast differentiation by inhibiting the RANKL-induced activation of PPAR-γ. Given the role of the PPAR-γ/cFos (AP-1) pathway in regulating the transcription factor, NFATc1, the master regulator of osteoclastogenesis, further studies are warranted to explore CO in treating inflammatory bone disorders.

Downregulation of Receptor Activator of Nuclear Factor kB Ligand (RANKL) in Chronic Myeloid Leukemia Patients Receiving Imatinib Mesylate Is Dose-Dependent.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4786-4786
Author(s):  
Francesco Albano ◽  
Antonella Zagaria ◽  
Luisa Anelli ◽  
Maria Guastadisegni ◽  
Alessandra Pannunzio ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Myeloid Leukemia ◽  
Imatinib Treatment ◽  
Nuclear Factor ◽  
Rankl Expression ◽  
Standard Dosage ◽  
Receptor Activator ◽  
High Doses ◽  
Nuclear Factor Kb

Abstract The receptor activator of the nuclear factor kB ligand (RANKL) is a key molecule in the pathogenesis of malignant osteolytic lesions in multiple myeloma or bone metastases in prostate and breast cancer. Inhibition of RANKL is therefore a promising new therapy for controlling bone loss and pain in bone tumors and associated osteolysis. Changes in bone and mineral metabolism developing in a proportion of patients taking imatinib for either chronic myeloid leukemia (CML) or gastrointestinal stromal tumors have previously been described. The aim of our study was to verify in CML patients the effect of imatinib on RANKL bone marrow molecular expression. The study included 13 CML patients (7 males, 6 females, median age 37 yrs). Six were treated with imatinib at standard dosage (400 mg) and the remaining 7 at higher doses (> 400 mg). The median duration of imatinib therapy was 28 months (range 13 – 44 months). The RANKL gene expression level was determined by Real-Time PCR using 1X Platinum SYBR Green qPCR SuperMix-UDG. Variations in RANKL gene expression level were estimated by comparing the values of 2−Δ Δ Ct obtained in CML patients at diagnosis and during imatinib treatment. For each of the tested cases the sample at diagnosis was utilized as calibrator and 28S rRNA was used as reference gene. Eight (62%) patients showed a downregulation of RANKL gene expression, the fold decrease ranging from 0.01 to 0.47 as compared to the value at diagnosis; among these 8 patients, 6 (75%) were treated with imatinib at standard dosage. Instead, 5 (38%) patients showed an upregulation of RANKL, the gene expression fold increase ranging from 1.43 to 4.94 as compared to the gene level observed at CML onset; all these 5 patients were treated with high doses of imatinib. There was no association between RANKL expression and the duration of imatinib treatment. These findings suggest that imatinib mesylate could control RANKL expression. At standard dosage, imatinib can downregulate RANKL production. The RANKL upregulation observed in CML patients treated with high doses of imatinib could be explained by the possible activation of the immune system cells, such as T and B cells, induced by the tyrosine kinases inhibitor. Further studies are needed to verify the minimal effective dose of imatinib on RANKL expression, with the aim of administering it as an antiosteolytic agent in such diseases as osteoporosis, metastatic bone disease, and multiple myeloma.

scholarly journals From Osteoclast Differentiation to Osteonecrosis of the Jaw: Molecular and Clinical Insights

2019 ◽  
Vol 20 (19) ◽  
pp. 4925 ◽  
Author(s):  
Anesi ◽  
Generali ◽  
Sandoni ◽  
Pozzi ◽  
Grande
Keyword(s):  
Bone Remodelling ◽  
Osteoclast Differentiation ◽  
Osteonecrosis Of The Jaw ◽  
Pathological State ◽  
Bone Homeostasis ◽  
Related Factors ◽  
Receptor Activator ◽  
Stimulating Factor ◽  
Perfect Space ◽  
Bone Physiology

Bone physiology relies on the delicate balance between resorption and formation of its tissue. Bone resorption depends on a process called osteoclastogenesis in which bone-resorbing cells, i.e., osteoclasts, are produced by the differentiation of more undifferentiated progenitors and precursors. This process is governed by two main factors, monocyte colony-stimulating factor (M-CSF) and receptor activator of NFκB ligand (RANKL). While the former exerts a proliferating effect on progenitors/precursors, the latter triggers a differentiation effect on more mature cells of the same lineage. Bone homeostasis requires a perfect space–time coordination of the involved signals. When osteoclastogenesis is poorly balanced with the differentiation of the bone forming counterparts, i.e., osteoblasts, physiological bone remodelling can turn into a pathological state, causing the systematic disruption of bone tissue which results in osteopenia or osteolysis. Examples of these conditions are represented by osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. Therefore, drugs targeting osteoclastogenesis, such as bisphosphonates and an anti-RANKL monoclonal antibody, have been developed and are currently used in the treatment of such diseases. Despite their demonstrated therapeutic efficacy, these agents are unfortunately not devoid of side effects. In this regard, a condition called osteonecrosis of the jaw (ONJ) has been recently correlated with anti-resorptive therapy. In this review we will address the involvement of osteoclasts and osteoclast-related factors in the pathogenesis of ONJ. It is to be hoped that a better understanding of the biological mechanisms underlying bone remodelling will help in the design a medical therapeutic approach for ONJ as an alternative to surgical procedures.

scholarly journals Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 196-207 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Yu Chen ◽  
Owen Stephens ◽  
Nathan Brown ◽  
Bangzheng Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Protein Production ◽  
Osteoclast Differentiation ◽  
Bone Lesions ◽  
Dependent Manner ◽  
Rankl Expression ◽  
Receptor Activator ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell–derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios.

Hypoxia is a potent inducer of the iron masterswitch hepcidin via Signal Transducer and Activator of Transcription 3 (STAT3)

2017 ◽  
Author(s):  
I Silva ◽  
V Rausch ◽  
T Peccerella ◽  
G Millonig ◽  
HK Seitz ◽  
...  
Keyword(s):  
Signal Transducer ◽  
Potent Inducer ◽  
Transcription 3
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