scholarly journals Binding Immunoglobulin Protein ( BIP ) Inhibits TNF ‐α–Induced Osteoclast Differentiation and Systemic Bone Loss in an Erosive Arthritis Model

2019 ◽  
Author(s):  
Mario M. Zaiss ◽  
Christopher Hall ◽  
Neil W. A. McGowan ◽  
Rebecca Babb ◽  
Vikesh Devlia ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Arthritis Model ◽  
Erosive Arthritis ◽  
Tnf Α ◽  
Systemic Bone Loss

scholarly journals Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

2013 ◽  
Vol 74 (1) ◽  
pp. 220-226 ◽  
Author(s):  
Emmanuel Coste ◽  
Iain R Greig ◽  
Patrick Mollat ◽  
Lorraine Rose ◽  
Mohini Gray ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Loss ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Joint Destruction ◽  
Luciferase Reporter ◽  
Collagen Induced Arthritis ◽  
Arthritis Model ◽  
Anti Inflammatory ◽  
Systemic Bone Loss

IntroductionInflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.MethodsThe inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.ResultsThe ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.ConclusionsHere we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.

TNF-α antibodies and osteoprotegerin decrease systemic bone loss associated with inflammation through distinct mechanisms in collagen-induced arthritis

Bone ◽  
2004 ◽  
Vol 35 (5) ◽  
pp. 1200-1207 ◽  
Author(s):  
N. Saidenberg-Kermanac'h ◽  
A. Corrado ◽  
D. Lemeiter ◽  
M.C. deVernejoul ◽  
M.C. Boissier ◽  
...  
Keyword(s):  
Bone Loss ◽  
Collagen Induced Arthritis ◽  
Tnf Α ◽  
Systemic Bone Loss

scholarly journals CS-semi5 Inhibits NF-κB Activation to Block Synovial Inflammation, Cartilage Loss and Bone Erosion Associated With Collagen-Induced Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiang Li ◽  
Xiaonan Tang ◽  
Yufei Wang ◽  
Changwei Chai ◽  
Zhehui Zhao ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Synovial Inflammation ◽  
Systemic Autoimmune Disease ◽  
Dependent Manner ◽  
Collagen Induced Arthritis ◽  
Positive Effects ◽  
Tnf Α ◽  
Cartilage Erosion

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that affects 1% of the population. CS-semi5 is a semisynthetic chondroitin sulfate. In this study, CS-semi5 was shown to have positive effects on a model of collagen-induced arthritis (CIA). CS-semi5 treatment had obvious effects on weight loss and paw swelling in CIA mice. Post-treatment analysis revealed that CS-semi5 alleviated three main pathologies (i.e., synovial inflammation, cartilage erosion and bone loss) in a dose-dependent manner. Further study showed that CS-semi5 could effectively reduce TNF‐α and IL‐1β production in activated macrophages via the NF‐κB pathway. CS-semi5 also blocked RANKL-trigged osteoclast differentiation from macrophages. Therefore, CS-semi5 may effectively ameliorate synovial inflammation, cartilage erosion and bone loss in RA through NF-κB deactivation.

scholarly journals Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 199
Author(s):  
Urara Tanaka ◽  
Shunichi Kajioka ◽  
Livia S. Finoti ◽  
Daniela B. Palioto ◽  
Denis F. Kinane ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Resorption ◽  
Bone Loss ◽  
Inflammatory Cytokines ◽  
Osteoclast Differentiation ◽  
Tartrate Resistant Acid Phosphatase ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Osteoblastic Cell Line ◽  
Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

scholarly journals Gram-positive bacteria cell wall-derived lipoteichoic acid induces inflammatory alveolar bone loss through prostaglandin E production in osteoblasts

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tsukasa Tominari ◽  
Ayumi Sanada ◽  
Ryota Ichimaru ◽  
Chiho Matsumoto ◽  
Michiko Hirata ◽  
...  
Keyword(s):  
Cell Wall ◽  
Bone Loss ◽  
Alveolar Bone ◽  
Osteoclast Differentiation ◽  
Lipoteichoic Acid ◽  
Alveolar Bone Loss ◽  
Gram Negative Bacteria ◽  
Gram Positive ◽  
Gram Negative ◽  
Gram Positive Bacteria

AbstractPeriodontitis is an inflammatory disease associated with severe alveolar bone loss and is dominantly induced by lipopolysaccharide from Gram-negative bacteria; however, the role of Gram-positive bacteria in periodontal bone resorption remains unclear. In this study, we examined the effects of lipoteichoic acid (LTA), a major cell-wall factor of Gram-positive bacteria, on the progression of inflammatory alveolar bone loss in a model of periodontitis. In coculture of mouse primary osteoblasts and bone marrow cells, LTA induced osteoclast differentiation in a dose-dependent manner. LTA enhanced the production of PGE2 accompanying the upregulation of the mRNA expression of mPGES-1, COX-2 and RANKL in osteoblasts. The addition of indomethacin effectively blocked the LTA-induced osteoclast differentiation by suppressing the production of PGE2. Using ex vivo organ cultures of mouse alveolar bone, we found that LTA induced alveolar bone resorption and that this was suppressed by indomethacin. In an experimental model of periodontitis, LTA was locally injected into the mouse lower gingiva, and we clearly detected alveolar bone destruction using 3D-μCT. We herein demonstrate a new concept indicating that Gram-positive bacteria in addition to Gram-negative bacteria are associated with the progression of periodontal bone loss.

Persistent Abnormal Immunocytes Induced Systemic Bone Loss in Locally Irradiated Rats

2021 ◽  
Author(s):  
Wei Hong ◽  
Lichen Tang ◽  
Rui Ge ◽  
Weiping Li ◽  
Xiaoyong Shen ◽  
...  
Keyword(s):  
Bone Loss ◽  
Systemic Bone Loss

scholarly journals Kalkitoxin Reduces Osteoclast Formation and Resorption and Protects against Inflammatory Bone Loss

2021 ◽  
Vol 22 (5) ◽  
pp. 2303
Author(s):  
Liang Li ◽  
Ming Yang ◽  
Saroj Kumar Shrestha ◽  
Hyoungsu Kim ◽  
William H. Gerwick ◽  
...  
Keyword(s):  
Bone Loss ◽  
Transmembrane Protein ◽  
Osteoclast Differentiation ◽  
Mapk Signaling ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Mineral Density ◽  
Multinucleated Cells

Osteoclasts, bone-specified multinucleated cells produced by monocyte/macrophage, are involved in numerous bone destructive diseases such as arthritis, osteoporosis, and inflammation-induced bone loss. The osteoclast differentiation mechanism suggests a possible strategy to treat bone diseases. In this regard, we recently examined the in vivo impact of kalkitoxin (KT), a marine product obtained from the marine cyanobacterium Moorena producens (previously Lyngbya majuscula), on the macrophage colony-stimulating factor (M-CSF) and on the receptor activator of nuclear factor κB ligand (RANKL)-stimulated in vitro osteoclastogenesis and inflammation-mediated bone loss. We have now examined the molecular mechanism of KT in greater detail. KT decreased RANKL-induced bone marrow-derived macrophages (BMMs) tartrate-resistant acid phosphatase (TRAP)-multinucleated cells at a late stage. Likewise, KT suppressed RANKL-induced pit area and actin ring formation in BMM cells. Additionally, KT inhibited several RANKL-induced genes such as cathepsin K, matrix metalloproteinase (MMP-9), TRAP, and dendritic cell-specific transmembrane protein (DC-STAMP). In line with these results, RANKL stimulated both genes and protein expression of c-Fos and nuclear factor of activated T cells (NFATc1), and this was also suppressed by KT. Moreover, KT markedly decreased RANKL-induced p-ERK1/2 and p-JNK pathways at different time points. As a result, KT prevented inflammatory bone loss in mice, such as bone mineral density (BMD) and osteoclast differentiation markers. These experiments demonstrated that KT markedly inhibited osteoclast formation and inflammatory bone loss through NFATc1 and mitogen-activated protein kinase (MAPK) signaling pathways. Therefore, KT may have potential as a treatment for destructive bone diseases.

scholarly journals Inhibitory Effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside on RANKL-Induced Osteoclast Differentiation and ROS Generation in Macrophages

2020 ◽  
Vol 22 (1) ◽  
pp. 222
Author(s):  
Eun-Nam Kim ◽  
Ga-Ram Kim ◽  
Jae Sik Yu ◽  
Ki Hyun Kim ◽  
Gil-Saeng Jeong
Keyword(s):  
Bone Loss ◽  
Bone Formation ◽  
Bone Disease ◽  
Osteoclast Differentiation ◽  
Inhibitory Effect ◽  
Bone Diseases ◽  
Ros Generation ◽  
Bone Homeostasis ◽  
Disease Treatment ◽  
And Migration

In bone homeostasis, bone loss due to excessive osteoclasts and inflammation or osteolysis in the bone formation process cause bone diseases such as osteoporosis. Suppressing the accompanying oxidative stress such as ROS in this process is an important treatment strategy for bone disease. Therefore, in this study, the effect of (2R)-4-(4-hydroxyphenyl)-2-butanol 2-O-β-d-apiofuranosyl-(1→6)-β-d-glucopyranoside (BAG), an arylbutanoid glycoside isolated from Betula platyphylla var. japonica was investigated in RANKL-induced RAW264.7 cells and LPS-stimulated MC3E3-T1 cells. BAG inhibited the activity of TRAP, an important marker of osteoclast differentiation and F-actin ring formation, which has osteospecific structure. In addition, the protein and gene levels were suppressed of integrin β3 and CCL4, which play an important role in the osteoclast-induced bone resorption and migration of osteoclasts, and inhibited the production of ROS and restored the expression of antioxidant enzymes such as SOD and CAT lost by RANKL. The inhibitory effect of BAG on osteoclast differentiation and ROS production appears to be due to the inhibition of MAPKs phosphorylation and NF-κβ translocation, which play a major role in osteoclast differentiation. In addition, BAG inhibited ROS generated by LPS and effectively restores the mineralization of lost osteoblasts, thereby showing the effect of bone formation in the inflammatory situation accompanying bone loss by excessive osteoclasts, suggesting its potential as a new natural product-derived bone disease treatment.

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