The p38α MAPK pathway in osteoblasts contributes to ovariectomy-induced bone loss by upregulating interleukin 6 expression

2013 ◽  
Author(s):  
Cyril Thouverey ◽  
Joseph Caverzasio
Keyword(s):  
Bone Loss ◽  
Interleukin 6 ◽  
Mapk Pathway ◽  
P38α Mapk

Effect of Icariin on Osteoclasts and Its Mechanism

2020 ◽  
Vol 10 (12) ◽  
pp. 1807-1812
Author(s):  
Xiaoxiao Wu ◽  
Xi Fu ◽  
Xiabing Qin
Keyword(s):  
Transcription Factors ◽  
Bone Resorption ◽  
Bone Loss ◽  
Mapk Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Therapeutic Drug ◽  
Actin Ring ◽  
B Subunit

Background: The paper aimed to elucidate the molecular mechanism of Icariin regulating RANKLinduced osteoclast-ogenesis and bone resorption, and to investigate whether Icariin could be a potential therapeutic drug for diseases of bone loss related to osteoclast. Material and methods: Osteoclasts were cultured. MTT to determine cell viability. Von Kossa to determine the effect of Icariin on bone resorption. F-actin ring staining to measure the expressions of various proteins, and WB method was used to measure the expression of p-65. Results: MTT showed that Icariin is not toxic to osteoclasts. The bone resorption result showed that RANKL-mediated osteoclast bone resorption was reduced in the early stage, and the higher the intervention concentration, the smaller the bone resorption area. F-actin ring staining indicated that it is possible to reduce the differentiation and bone resorption capacity of osteoclasts by hindering the formation of F-actin ring in the early stage, and in a concentration-dependentmanner. Significantly reduced the expressions of key transcription factors-NFATc1 and c-Fos. It significantly inhibited the phosphorylation and nucleation of NF-κB subunit p65 induced by RANKL, and significantly inhibited the phosphorylation of ERK and p38 proteins in the MAPK pathway activated by RANKL. Conclusion: Icariin can effectively inhibit osteoclast differentiation, F-actin ring formation, and bone resorption. By inhibiting the key transcription factors NFATc1 and c-Fos to down-regulate related expressions, thereby impeding osteoclast differentiation, Icariin may regulate key transcription factors NFATc1 and c-Fos through NF-κB and MAPK signaling pathways. Studies have suggested that Icariin could be a potential treatment for diseases of bone loss related to osteoclasts.

scholarly journals The multi-site docking protein Grb2-associated binder 1 (Gab1) enhances interleukin-6-induced MAPK-pathway activation in an SHP2-, Grb2-, and time-dependent manner

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Hannes Bongartz ◽  
Karen Gille ◽  
Wiebke Hessenkemper ◽  
Katharina Mandel ◽  
Marc Lewitzky ◽  
...  
Keyword(s):  
Interleukin 6 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Sh2 Domain ◽  
Time Dependent ◽  
Signalling Pathways ◽  
Dependent Manner ◽  
Mapk Activation ◽  
Pathway Activation ◽  
Mapk Signalling

Abstract Background Cytokine-dependent activation of signalling pathways is tightly orchestrated. The spatiotemporal activation of signalling pathways dictates the specific physiological responses to cytokines. Dysregulated signalling accounts for neoplastic, developmental, and inflammatory diseases. Grb2-associated binder (Gab) family proteins are multi-site docking proteins, which expand cytokine-induced signal transduction in a spatial- and time-dependent manner by coordinating the recruitment of proteins involved in mitogen activated protein kinase (MAPK)/extracellular-signal regulated kinase (ERK) and phosphatidyl-inositol-3-kinase (PI3K) signalling. Interaction of Gab family proteins with these signalling proteins determines strength, duration and localization of active signalling cascades. However, the underlying molecular mechanisms of signal orchestration by Gab family proteins in IL-6-induced signalling are only scarcely understood. Methods We performed kinetic analyses of interleukin-6 (IL-6)-induced MAPK activation and analysed downstream responses. We compared signalling in wild-type cells, Gab1 knock-out cells, those reconstituted to express Gab1 mutants, and cells expressing gp130 receptors or receptor mutants. Results Interleukin-6-induced MAPK pathway activation can be sub-divided into an early Gab1-independent and a subsequent Gab1-dependent phase. Early Gab1-independent MAPK activation is critical for the subsequent initiation of Gab1-dependent amplification of MAPK pathway activation and requires binding of SH2 domain-containing phosphatase 2 (SHP2) to the interleukin-6 receptor complex. Subsequent and coordinated recruitment of Grb2 and SHP2 to Gab1 is essential for Gab1-dependent amplification of IL-6-induced late MAPK pathway activation and subsequent gene expression. Conclusions Overall, we elaborated the molecular requirements for Gab1-dependent, spatiotemporal orchestration of interleukin-6-dependent MAPK signalling. We discriminated IL-6-induced Gab1-independent, early activation of MAPK signalling and Gab1-dependent, sustained activation of MAPK signalling.

scholarly journals SLIT2 Overexpression in Periodontitis Intensifies Inflammation and Alveolar Bone Loss, Possibly via the Activation of MAPK Pathway

2020 ◽  
Vol 8 ◽  
Author(s):  
Liping Wang ◽  
Jing Zheng ◽  
Janak L. Pathak ◽  
Yunxin Chen ◽  
Dongliang Liang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Alveolar Bone ◽  
Mapk Pathway ◽  
Alveolar Bone Loss

scholarly journals Functional Block of Interleukin-6 Reduces a Bone Pain Marker But Not Bone Loss in Hindlimb-Unloaded Mice

2020 ◽  
Vol 21 (10) ◽  
pp. 3521 ◽  
Author(s):  
Hiroki Wakabayashi ◽  
Gaku Miyamura ◽  
Nobuto Nagao ◽  
Sho Kato ◽  
Yohei Naito ◽  
...  
Keyword(s):  
Bone Loss ◽  
Interleukin 6 ◽  
Inhibitory Effect ◽  
Mechanical Hyperalgesia ◽  
Tail Suspension ◽  
Micro Computed Tomography ◽  
Drg Neurons ◽  
Calcitonin Gene ◽  
Proximal Tibial Metaphyses ◽  
Von Frey Filaments

Interleukin-6 (IL-6) is widely accepted to stimulate osteoclasts. Our aim in this study was to examine whether the inhibitory effect of IL-6 on bone loss and skeletal pain associated with osteoporosis in hindlimb-unloaded (HU) mice in comparison with bisphosphonate. Eight-week-old male ddY mice were tail suspended for 2 weeks. Starting immediately after reload, vehicle (HU group), alendronate (HU-ALN group), or anti-IL-6 receptor antibody (HU-IL-6i group) was injected subcutaneously. After a 2-week treatment, pain-related behavior was examined using von Frey filaments. The bilateral distal femoral and proximal tibial metaphyses were analyzed three-dimensionally with micro-computed tomography. Calcitonin gene-related peptide (CGRP) expressions in dorsal root ganglion (DRG) neurons innervating the hindlimbs were examined using immunohistochemistry. HU mice with tail suspension developed bone loss. The HU mice showed mechanical hyperalgesia in the hindlimbs and increased CGRP immunoreactive neurons in the L3-5 DRG. Treatment with IL-6i and ALN prevented HU-induced mechanical hyperalgesia and upregulation of CGRP expressions in DRG neurons. Furthermore, ALN but not IL-6i prevented HU-induced bone loss. In summary, treatment with IL-6i prevented mechanical hyperalgesia in hindlimbs and suppressed CGRP expressions in DRG neurons of osteoporotic models. The novelty of this research suggests that IL-6 is one of the causes of immobility-induced osteoporotic pain regardless improvement of bone loss.

scholarly journals Association of the G-174C Variant in the Interleukin-6 Promoter Region With Bone Loss and Fracture Risk in Older Women

2004 ◽  
Vol 19 (10) ◽  
pp. 1612-1618 ◽  
Author(s):  
Susan P Moffett ◽  
Joseph M Zmuda ◽  
Jane A Cauley ◽  
Katie L Stone ◽  
Michael C Nevitt ◽  
...  
Keyword(s):  
Bone Loss ◽  
Fracture Risk ◽  
Older Women ◽  
Interleukin 6 ◽  
Promoter Region

Protein kinase C δ and η isoenzymes control the shedding of the interleukin 6 receptor α in myeloma cells

2001 ◽  
Vol 358 (1) ◽  
pp. 193-200 ◽  
Author(s):  
Wilfrid THABARD ◽  
Madeleine COLLETTE ◽  
Régis BATAILLE ◽  
Martine AMIOT
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Interleukin 6 ◽  
Mapk Pathway ◽  
Tumour Progression ◽  
Specific Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Kinase C ◽  
Interleukin 6 Receptor

The soluble interleukin 6 receptor α is an agonistic molecule of interleukin 6 (IL-6) and is important in the biology of multiple myeloma. More precisely, it potentiates the deleterious effects of IL-6 during tumour progression, facilitating angiogenesis and bone resorption. Because the mechanisms involved in the shedding of the interleukin 6 receptor α (IL-6Rα) in multiple myeloma are not known, we have investigated them in the XG-6 human myeloma cell line. Here we provide evidence that PMA-induced IL-6Rα shedding is controlled by a metalloproteinase and by protein kinase C (PKC) isoenzymes that do not require Ca2+ for their activation. We show that XG-6 cells express PKC-δ, −η and −∊ isoenzymes. However, after stimulation with PMA, only PKC-δ and PKC-η are activated, as shown by their translocation to the membrane. Treatment with PMA induces an increase in PKC-δ phosphorylation in its active loop. In addition, by using rottlerin, a specific inhibitor of PKC-δ, we demonstrate that PKC-δ is involved in the PMA-induced shedding of IL-6Rα. With the use of UO126, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway, we show that the PMA-induced IL-6Rα shedding is mediated in part by the MAPK pathway. Finally, whereas GF109203X, a general PKC inhibitor, inhibits the activation of ERK1/2 (extracellular signal-regulated protein kinase 1/2), rottlerin has no inhibitory effect, indicating that the Ras/MAPK activation is PKC-dependent but PKC-δ-independent. Taken together, these results suggest that the PMA-induced shedding of IL-6Rα is mediated by a PKC isoenzyme network.

scholarly journals Interleukin-6 Knockout Inhibits Senescence of Bone Mesenchymal Stem Cells in High-Fat Diet-Induced Bone Loss

2021 ◽  
Vol 11 ◽  
Author(s):  
Yujue Li ◽  
Lingyun Lu ◽  
Ying Xie ◽  
Xiang Chen ◽  
Li Tian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Loss ◽  
Interleukin 6 ◽  
High Fat Diet ◽  
Cell Senescence ◽  
Low Grade ◽  
High Fat ◽  
Bone Mesenchymal Stem Cells

Obesity, a chronic low-grade inflammatory state, not only promotes bone loss, but also accelerates cell senescence. However, little is known about the mechanisms that link obesity, bone loss, and cell senescence. Interleukin-6 (IL-6), a pivotal inflammatory mediator increased during obesity, is a candidate for promoting cell senescence and an important part of senescence-associated secretory phenotype (SASP). Here, wild type (WT) and (IL-6 KO) mice were fed with high-fat diet (HFD) for 12 weeks. The results showed IL-6 KO mice gain less weight on HFD than WT mice. HFD induced trabecular bone loss, enhanced expansion of bone marrow adipose tissue (BMAT), increased adipogenesis in bone marrow (BM), and reduced the bone formation in WT mice, but it failed to do so in IL-6 KO mice. Furthermore, IL-6 KO inhibited HFD-induced clone formation of bone marrow cells (BMCs), and expression of senescence markers (p53 and p21). IL-6 antibody inhibited the activation of STAT3 and the senescence of bone mesenchymal stem cells (BMSCs) from WT mice in vitro, while rescued IL-6 induced senescence of BMSCs from IL-6 KO mice through the STAT3/p53/p21 pathway. In summary, our data demonstrated that IL-6 KO may maintain the balance between osteogenesis and adipogenesis in BM, and restrain senescence of BMSCs in HFD-induced bone loss.

scholarly journals Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.

1994 ◽  
Vol 13 (5) ◽  
pp. 1189-1196 ◽  
Author(s):  
V. Poli ◽  
R. Balena ◽  
E. Fattori ◽  
A. Markatos ◽  
M. Yamamoto ◽  
...  
Keyword(s):  
Bone Loss ◽  
Interleukin 6 ◽  
Estrogen Depletion ◽  
Deficient Mice
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