scholarly journals The Death Receptor 3–TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

2008 ◽  
Vol 205 (11) ◽  
pp. 2457-2464 ◽  
Author(s):  
Melanie Jane Bull ◽  
Anwen Siân Williams ◽  
Zarabeth Mecklenburgh ◽  
Claudia Jane Calder ◽  
Jason Peter Twohig ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Joint Destruction ◽  
Death Receptor ◽  
Bone Destruction ◽  
Chronic Inflammatory Disease ◽  
Joint Disease ◽  
Bone Pathology ◽  
Novel Target ◽  
Death Receptor 3

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint disease.

scholarly journals Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis

Rheumatology ◽  
2020 ◽  
Author(s):  
Shixian Chen ◽  
Chunqing Guo ◽  
Ran Wang ◽  
Zhitao Feng ◽  
Zheng Liu ◽  
...  
Keyword(s):  
Mouse Models ◽  
Th17 Cells ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Suppressor Cells ◽  
Th 17 ◽  
Autoimmune Conditions

Abstract Objectives While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. Methods We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. Results Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. Conclusion Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

scholarly journals Effect of Angiotensin II on Bone Erosion and Systemic Bone Loss in Mice with Tumor Necrosis Factor-Mediated Arthritis

2020 ◽  
Vol 21 (11) ◽  
pp. 4145 ◽  
Author(s):  
Takahiko Akagi ◽  
Tomoyuki Mukai ◽  
Takafumi Mito ◽  
Kyoko Kawahara ◽  
Shoko Tsuji ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tumor Necrosis Factor ◽  
Bone Loss ◽  
Tumor Necrosis ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Ang Ii ◽  
Necrosis Factor ◽  
Systemic Bone Loss

Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), which regulates the cardiovascular system. The RAS is reportedly also involved in bone metabolism. The upregulation of RAS components has been shown in arthritic synovial tissues, suggesting the potential involvement of Ang II in arthritis. Accordingly, in the present study, we investigated the role of Ang II in bone erosion and systemic bone loss in arthritis. Ang II was infused by osmotic pumps in tumor necrosis factor-transgenic (TNFtg) mice. Ang II infusion did not significantly affect the severity of clinical and histological inflammation, whereas bone erosion in the inflamed joints was significantly augmented. Ang II administration did not affect the bone mass of the tibia or vertebra. To suppress endogenous Ang II, Ang II type 1 receptor (AT1R)-deficient mice were crossed with TNFtg mice. Genetic deletion of AT1R did not significantly affect inflammation, bone erosion, or systemic bone loss. These results suggest that excessive systemic activation of the RAS can be a risk factor for progressive joint destruction. Our findings indicate an important implication for the pathogenesis of inflammatory bone destruction and for the clinical use of RAS inhibitors in patients with rheumatoid arthritis.

scholarly journals Targeting of Phospholipase D1 Ameliorates Collagen-Induced Arthritis via Modulation of Treg and Th17 Cell Imbalance and Suppression of Osteoclastogenesis

2020 ◽  
Vol 21 (9) ◽  
pp. 3230
Author(s):  
Hyun Jung Yoo ◽  
Won Chan Hwang ◽  
Do Sik Min
Keyword(s):  
Autoimmune Diseases ◽  
Cell Population ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Bone Erosion ◽  
Bone Destruction ◽  
Systemic Autoimmune Disease ◽  
Collagen Induced Arthritis ◽  
Phospholipase D1

Phospholipase D1 (PLD1) plays a crucial role in various inflammatory and autoimmune diseases. Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease. However, the role of PLD1 in the pathogenesis of RA remains unknown. Here, we first investigated the role and effects of PLD1 in collagen-induced arthritis (CIA) and found that genetic and pharmacological inhibition of PLD1 in DBA1/J mice with CIA reduced the incidence of CIA, decreased the clinical score, and abrogated disease symptoms including infiltration of leukocytes, synovial inflammation, bone erosion, and cartilage destruction. Moreover, ablation and inhibition of PLD1 suppressed the production of type II collagen-specific IgG2a autoantibody and proinflammatory cytokines, accompanied by an increase in the regulatory T (Treg) cell population and a decrease in the Th17 cell population in CIA mice. The PLD1 inhibitor also promoted differentiation of Treg cells and suppressed differentiation of Th17 cells in vitro. Furthermore, the PLD1 inhibitor attenuated pathologic bone destruction in CIA mice by suppressing osteoclastogenesis and bone resorption. Thus, our findings indicate that the targeting of PLD1 can ameliorate CIA by modulating the imbalance of Treg and Th17 cells and suppressing osteoclastogenesis, which might be a novel strategy to treat autoimmune diseases, such as RA.

scholarly journals Non-classical monocytes as mediators of tissue destruction in arthritis

2018 ◽  
Vol 77 (10) ◽  
pp. 1490-1497 ◽  
Author(s):  
Antonia Puchner ◽  
Victoria Saferding ◽  
Michael Bonelli ◽  
Yohei Mikami ◽  
Melanie Hofmann ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Joint Destruction ◽  
Joint Damage ◽  
Bone Destruction ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Monocyte Subsets ◽  
Tissue Destruction ◽  
Local Bone ◽  
Classical Monocytes

ObjectivesBone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive.MethodsWe investigated CCR2−/− mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis.ResultsWe show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL.ConclusionTherefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage.

scholarly journals S100A8/A9 is not essential for the development of inflammation and joint pathology in interleukin-1 receptor antagonist knockout mice

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Irene Di Ceglie ◽  
Peter L. E. M. van Lent ◽  
Edwin J. W. Geven ◽  
Marije I. Koenders ◽  
Arjen B. Blom ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Receptor Antagonist ◽  
Bone Marrow Cells ◽  
Bone Erosion ◽  
Interleukin 1 ◽  
Joint Destruction ◽  
Bone Destruction ◽  
Joint Inflammation ◽  
Cartilage Degeneration ◽  
Old Mice

Abstract Background Excessive osteoclast activity, which is strongly stimulated by pro-inflammatory mediators, results in bone and cartilage degeneration as central features of many arthritides. Levels of the alarmin S100A8/A9 and interleukin (IL)-1β are both increased in arthritis patients and correlate with disease activity and progression of tissue erosion. We previously presented S100A8/A9 as a good biomarker for joint inflammation and arthritis pathology under circumstances of high IL-1 signaling in mice that lack the gene encoding IL-1 receptor antagonist (Il1rn−/− mice). Here, we investigated whether S100A8/A9 is also actively involved in the development of joint inflammation and both cartilage and bone pathology under these conditions by comparing Il1rn−/− mice with mice that have an additional deficiency for S100a9 (Il1rn−/−XS100a9−/−). Methods Il1rn−/−XS100a9−/− on a BALB/c background were obtained by crossing S100a9−/− mice and Il1rn−/− mice. Arthritis incidence and severity were macroscopically scored. Myeloid cell populations in the bone marrow and spleen were determined using flow cytometry. In vitro osteoclastogenesis of bone marrow cells was evaluated with TRAP staining. Microscopic joint inflammation, cartilage degeneration, and bone destruction were evaluated using histology of ankle joints of 12- and 20-week-old mice. Results Macroscopically scored arthritis severity was comparable between Il1rn−/− and Il1rn−/−XS100a9−/− mice. Inflammation, cartilage erosion, and bone erosion were clearly present in 12-week-old mice of both strains lacking Il1rn−/−, but not significantly different between Il1rn−/−XS100a9−/− and Il1rn−/−. Moreover, we observed that the numbers of neutrophils and monocytes were increased by the absence of Il1rn, which was affected by the absence of S100a9 only in the spleen but not in the bone marrow. In line with our other findings, the absence of S100a9 did not affect the osteoclastogenic potential of osteoclast precursors in the absence of Il1rn. Finally, in agreement with the findings in early arthritis development in 12-week-old mice, cartilage and bone erosion in 20-week-old mice was significantly higher in both Il1rn−/− strains, but the additional absence of S100a9 did not further affect tissue pathology. Conclusion S100A8/A9 deficiency does not significantly affect inflammation and joint destruction in mice with high IL1β signaling suggesting that S100A8/A9 is not essential for the development of arthritis under these conditions.

scholarly journals Expression of death receptor-3 in human breast cancer and its functional effects on breast cancer cells in vitro

2013 ◽  
Vol 29 (4) ◽  
pp. 1356-1364 ◽  
Author(s):  
ZHICHENG GE ◽  
ANDREW J. SANDERS ◽  
LIN YE ◽  
ROBERT E. MANSEL ◽  
WEN G. JIANG
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Human Breast Cancer ◽  
Breast Cancer Cells ◽  
Death Receptor ◽  
Human Breast ◽  
Death Receptor 3

scholarly journals Cervus and cucumis peptides ameliorates bone erosion in experimental arthritis by inhibiting osteoclastogenesis

2019 ◽  
Vol 6 (1) ◽  
pp. e000331 ◽  
Author(s):  
Ze-Min Lin ◽  
Yu-Ting Liu ◽  
Yan-Sheng Xu ◽  
Xiao-Qian Yang ◽  
Feng-Hua Zhu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Experimental Arthritis ◽  
Raw264.7 Cells ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Therapeutic Benefits

ObjectiveRheumatoid arthritis is an autoimmune disease characterised by inflammation and bone loss, leading to joint destruction and deformity. The cervus and cucumis polypeptide (CCP) injection, one of the traditional Chinese medicine injections combined extracts from deer horn and sweet melon seeds, is widely used to treat arthritis and bone fracture in China. The present study investigated the therapeutic efficacy and mechanism of CCP on pathological immune cells and bone homoeostasis in rodent experimental arthritis.MethodsThe effects of CCP (4 mg/kg and 2 mg/kg) on clinical arthritis symptoms, bone erosion, proinflammatory cytokines and pathological immune cells induced by complete Freund’s adjuvant was evaluated in male Sprague-Dawley rats. The impacts of CCP (2 mg/kg) on joint erythema and swelling, production of pathogenic antibodies and the proportion of inflammatory cells were assessed in collagen-induced arthritis (CIA) in DBA/1J mice. Regulation of osteoclastogenesis by CCP was observed in the murine macrophage-like RAW264.7 cells treated with receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF).ResultsCCP administration significantly prevented disease progression in both adjuvant-induced arthritis (AIA) rats and CIA mice. The therapeutic benefits were accompanied by reduction of paw oedema, reversed bone destruction, decreased pathological changes and osteoclast numbers in joints in AIA rats, as well as attenuated clinical manifestation and autoantibodies production in CIA mice. Meanwhile, in vitro supplemented of CCP concentration dependently inhibited RANKL/M-CSF-induced osteoclast differentiation, without showing cytotoxicity in RAW264.7 cells. Further, the presence of CCP dampened the augmented downstream signalling transduction as well as activation of osteoclast-specific genes and transcription factors induced by RANKL/M-CSF in RAW264.7 cells.ConclusionOur study suggested that the therapeutic effects of CCP in experimental arthritis could be attributed to its intervention on RANKL-induced osteoclastogenesis signalling pathway in osteoclast precursor cells.

scholarly journals Caspase-8: A Novel Target to Overcome Resistance to Chemotherapy in Glioblastoma

2018 ◽  
Vol 19 (12) ◽  
pp. 3798 ◽  
Author(s):  
Giulia Fianco ◽  
Claudia Contadini ◽  
Alessandra Ferri ◽  
Claudia Cirotti ◽  
Venturina Stagni ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Death Receptor ◽  
Cellular Systems ◽  
Caspase 8 ◽  
Cancer Resistance ◽  
Inhibitory Protein ◽  
Novel Target

Caspase-8 was originally identified as a central player of programmed cell death triggered by death receptor stimulation. In that context, its activity is tightly regulated through several mechanisms, with the best established being the expression of FLICE-like inhibitory protein (FLIP) family proteins and the Src-dependent phosphorylation of Caspase-8 on Tyr380. Loss of apoptotic signaling is a hallmark of cancer and indeed Caspase-8 expression is often lost in tumors. This event may account not only for cancer progression but also for cancer resistance to radiotherapy and chemotherapy. Intriguingly, other tumors, such as glioblastoma, preferentially retain Caspase-8 expression, and high levels of Caspase-8 expression may correlate with a worse prognosis, suggesting that in this context this protease loses its apoptotic activity and gains additional functions. Using different cellular systems, it has been clearly shown that in cancer Caspase-8 can exhibit non-canonical functions, including promotion of cell adhesion, migration, and DNA repair. Intriguingly, in glioblastoma models, Caspase-8 can promote NF-κB-dependent expression of several cytokines, angiogenesis, and in vitro and in vivo tumorigenesis. Overall, these observations suggest that some cancer cells may hijack Caspase-8 function which in turn promote cancer progression and resistance to therapy. Here we aim to highlight the multiple functions of Caspase-8 and to discuss whether the molecular mechanisms that modulate the balance between those functions may be targeted to dismantle the aberrant activity of Caspase-8 and to restore its canonical apoptotic functionality.

scholarly journals Inhibition of Rheumatoid Arthritis Using Bark, Leaf, and Male Flower Extracts of Eucommia ulmoides

2020 ◽  
Vol 2020 ◽  
pp. 1-11 ◽  
Author(s):  
Yun-Yun Xing ◽  
Jian-Ying Wang ◽  
Kai Wang ◽  
Yan Zhang ◽  
Kun Liu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Erosion ◽  
Bone Destruction ◽  
Male Flower ◽  
Joint Inflammation ◽  
Inflammatory Factors ◽  
Enzyme Linked Immunosorbent Assay ◽  
Eucommia Ulmoides

Eucommia ulmoides Oliv., a native Chinese plant species, has been used as a traditional Chinese medicine formulation to treat rheumatoid arthritis (RA), strengthen bones and muscles, and lower blood pressure. Various parts of this plant such as the bark, leaves, and flowers have been found to have anti-inflammatory properties. E. ulmoides has potential applications as a therapeutic agent against bone disorders, which were investigated in this study. In vitro, RA joint fibroblast-like synoviocytes (RA-FLS) were treated with different concentrations (0, 25, 50, 100, 200, 400, 800, and 1000 μg/mL) of E. ulmoides bark, leaf, and male flower alcoholic extracts (EB, EL, and EF, respectively) to determine their potential cytotoxicity. Tumor necrosis factor- (TNF-) α and nitric oxide (NO) levels in RA-FLS were quantified using enzyme-linked immunosorbent assay (ELISA). Furthermore, collagen-induced arthritis (CIA) rats were treated with EB, EL, EF, Tripterygium wilfordii polyglycoside (TG) or the normal control (Nor), and then ankle joint pathology, bone morphology, and serum and spleen inflammatory cytokine levels were evaluated. The results showed that, in RA-FLS, EB, EL, and EF were not cytotoxic; EB and EF reduced TNF-α supernatant levels; and EB, EL, and EF reduced NO levels. The results of in vivo experiments showed that EB, EL, and EF alleviated ankle swelling and joint inflammation, while all extracts diminished inflammatory cell infiltration, pannus and bone destruction, and bone erosion. All tested extracts inhibited interleukin- (IL-) 6, IL-17, and TNF-α mRNA in the spleen of CIA rats, while EB most effectively reduced osteoclasts and inhibited bone erosion. EF showed the most obvious inhibition of inflammatory factors and pannus. Thus, EB, EL, and EF may alleviate bone destruction by inhibiting inflammation.

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