scholarly journals Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

2014 ◽  
Vol 89 (1) ◽  
pp. 581-593 ◽  
Author(s):  
Weiqiang Chen ◽  
Suan-Sin Foo ◽  
Adam Taylor ◽  
Aleksei Lulla ◽  
Andres Merits ◽  
...  
Keyword(s):  
Bone Loss ◽  
Chikungunya Virus ◽  
Nuclear Factor Κb ◽  
Unique Role ◽  
Tibial Epiphysis ◽  
Chemotactic Protein ◽  
Ankle Joints ◽  
Receptor Activator ◽  
Cellular Recruitment ◽  
Bone Resorbing Osteoclast

ABSTRACTThe recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (μCT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss.IMPORTANCEArthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

scholarly journals Lack of NOD2 attenuates ovariectomy-induced bone loss via inhibition of osteoclasts

2017 ◽  
Vol 235 (2) ◽  
pp. 85-96 ◽  
Author(s):  
Ke Ke ◽  
Ok-Joo Sul ◽  
Soo-Wol Chung ◽  
Jae-Hee Suh ◽  
Hye-Seon Choi
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Kappa B ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Nuclear Factor ◽  
Oxygen Species ◽  
Receptor Activator ◽  
Recognition Receptor ◽  
Oligomerization Domain

Nucleotide-binding oligomerization domain-2 (NOD2) is a pattern recognition receptor of the innate immune system. It interacts with serine–threonine kinases to induce activation of nuclear factor κB (NF-κB), which is important for receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. We tested the idea that NOD2 modulates bone metabolism via an action on osteoclasts (OCs). The absence of NOD2 reduced ovariectomy-induced bone loss in mice, and lowered the area and the activity of OCs, by impairing RANKL signaling. It also reduced the level of reactive oxygen species (ROS), as well as of NF-κB-DNA binding upon RANKL exposure. NOD2 was found to physically interact with nicotinamide adenine dinucleotide phosphate oxidase 1, and this led to increased production of ROS in OCs. Our data suggest that NOD2 contributes to bone loss in estrogen deficiency by elevating ROS levels in OCs.

scholarly journals T-cell receptor activator of nuclear factor-κB ligand/osteoprotegerin imbalance is associated with HIV-induced bone loss in patients with higher CD4+ T-cell counts

AIDS ◽  
2018 ◽  
Vol 32 (7) ◽  
pp. 885-894 ◽  
Author(s):  
Kehmia Titanji ◽  
Aswani Vunnava ◽  
Antonina Foster ◽  
Anandi N. Sheth ◽  
Jeffrey L. Lennox ◽  
...  
Keyword(s):  
T Cell ◽  
Bone Loss ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Cd4 T Cell ◽  
Nuclear Factor ◽  
Cell Counts ◽  
Receptor Activator

Retrovirus-Mediated Gene Transfer of Receptor Activator of Nuclear Factor-κB-Fc Prevents Bone Loss in Ovariectomized Mice

Stem Cells ◽  
2006 ◽  
Vol 24 (7) ◽  
pp. 1798-1805 ◽  
Author(s):  
Dohee Kim ◽  
Sun Wook Cho ◽  
Sun Ju Her ◽  
Jae Yun Yang ◽  
Sang Wan Kim ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Bone Loss ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ovariectomized Mice ◽  
Receptor Activator

scholarly journals Prolactin blocks the expression of receptor activator of nuclear factor κB ligand and reduces osteoclastogenesis and bone loss in murine inflammatory arthritis

2017 ◽  
Vol 19 (1) ◽  
Author(s):  
Maria G. Ledesma-Colunga ◽  
Norma Adán ◽  
Georgina Ortiz ◽  
Mariana Solís-Gutiérrez ◽  
Fernando López-Barrera ◽  
...  
Keyword(s):  
Bone Loss ◽  
Inflammatory Arthritis ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Receptor Activator

scholarly journals The Fungal Metabolite (+)-Terrein Abrogates Ovariectomy-Induced Bone Loss and Receptor Activator of Nuclear Factor-κB Ligand–Induced Osteoclastogenesis by Suppressing Protein Kinase-C α/βII Phosphorylation

2021 ◽  
Vol 12 ◽  
Author(s):  
Kyosuke Sakaida ◽  
Kazuhiro Omori ◽  
Masaaki Nakayama ◽  
Hiroki Mandai ◽  
Saki Nakagawa ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Metabolism ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Common Disease ◽  
Mouse Bone Marrow ◽  
Nuclear Factor ◽  
Receptor Activator

Osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture that results in fragility fractures. Severe bone loss due to osteoporosis triggers pathological fractures and consequently decreases the daily life activity and quality of life. Therefore, prevention of osteoporosis has become an important issue to be addressed. We have reported that the fungal secondary metabolite (+)-terrein (TER), a natural compound derived from Aspergillus terreus, has shown receptor activator of nuclear factor-κB ligand (RANKL)–induced osteoclast differentiation by suppressing nuclear factor of activated T-cell 1 (NFATc1) expression, a master regulator of osteoclastogenesis. TER has been shown to possess extensive biological and pharmacological benefits; however, its effects on bone metabolism remain unclear. In this study, we investigated the effects of TER on the femoral bone metabolism using a mouse-ovariectomized osteoporosis model (OVX mice) and then on RANKL signal transduction using mouse bone marrow macrophages (mBMMs). In vivo administration of TER significantly improved bone density, bone mass, and trabecular number in OVX mice (p < 0.01). In addition, TER suppressed TRAP and cathepsin-K expression in the tissue sections of OVX mice (p < 0.01). In an in vitro study, TER suppressed RANKL-induced phosphorylation of PKCα/βII, which is involved in the expression of NFATc1 (p < 0.05). The PKC inhibitor, GF109203X, also inhibited RANKL-induced osteoclastogenesis in mBMMs as well as TER. In addition, TER suppressed the expression of osteoclastogenesis-related genes, such as Ocstamp, Dcstamp, Calcr, Atp6v0d2, Oscar, and Itgb3 (p < 0.01). These results provide promising evidence for the potential therapeutic application of TER as a novel treatment compound against osteoporosis.

scholarly journals Correction for Chen et al., Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

2015 ◽  
Vol 89 (23) ◽  
pp. 12232-12232 ◽  
Author(s):  
Weiqiang Chen ◽  
Suan-Sin Foo ◽  
Adam Taylor ◽  
Aleksei Lulla ◽  
Andres Merits ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Virus Infection ◽  
Bone Loss ◽  
Chikungunya Virus ◽  
Monocyte Chemotactic Protein ◽  
Chemotactic Protein

scholarly journals The PPAR-γ antagonist T007 inhibits RANKL-induced osteoclastogenesis and counteracts OVX-induced bone loss in mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiang Li ◽  
Lei Ning ◽  
Jianjun Ma ◽  
Ziang Xie ◽  
Xiangde Zhao ◽  
...  
Keyword(s):  
Bone Loss ◽  
Nuclear Factor Κb ◽  
In Vitro Assays ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Bone Damage ◽  
Receptor Activator ◽  
Cellular Components

Abstract Background Osteoclasts are key determinant cellular components implicated in the development and progression of disorders driven by bone damage. Herein, we studied the upshot of T007, an antagonist of peroxisome proliferator-activated receptor-gamma (PPARγ), on osteoclastogenesis using cell and animal models. Results The in vitro assays revealed that T007 hindered the osteoclastogenesis caused by the treatment with the receptor activator of nuclear factor-κB ligand (RANKL) through inhibiting the levels of PPARγ in cells. The PPARγ siRNA partially reproduced the inhibitory action of T007. The opposite findings were produced after PPARγ overexpression. Furthermore, T007 prevented from bone loss in a mouse model of osteoporosis induced by ovariectomy (OVX). These findings implied that T007 is a potential efficient drug for the prophylaxis and cure of osteoclast-related disorders. Conclusions Taken together, our findings demonstrated that T007 impedes osteoclastogenesis and will be useful for the therapy of bone related diseases, essentially osteoporosis.

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