scholarly journals Quantitative Proteomic Analysis of Bi Zhong Xiao Decoction Against Collagen-induced Arthritis Rats in the Early and Late Stages

2021 ◽  
Author(s):  
Cailin He ◽  
Yang Wang ◽  
Yuqi Wen ◽  
Teng Li ◽  
En Hu ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Proteomic Analysis ◽  
Early Stage ◽  
Receptor Interaction ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Weight Changes ◽  
Collagen Induced Arthritis ◽  
Anti Inflammatory ◽  
Late Stages

Abstract Background: Rheumatoid arthritis (RA) is a chronic, progressive, systemic autoimmune inflammatory disease. Bi Zhong Xiao decoction (BZXD) performs multiple functions for rheumatoid arthritis (RA) treatment for decades. In this study, we aimed to study the protein alterations of BZXD in the early and late stages of RA.Methods: Sprague-Dawley rats were randomly divided into the Control, collagen-induced arthritis (CIA) and BZXD groups. Clinical assessment, paw thickness, weight changes and serum inflammatory cytokine levels were used to evaluate anti-inflammatory effects. Histopathological tests were performed to assess the improvement of inflammation and synovial hyperplasia. Moreover, we analyzed the proteins profiling of synovial tissue samples with different time intervals after BZXD treatment by Isobaric Tag for Relative Absolute (ITRAQ) quantitative proteomics technology. To further explore the interrelationships among differentially expressed proteins (DEPs), we used DAVID Bioinformatics Resources v6.8 and STRING 11.0 for bioinformatics analysis. Besides, western blot was exerted to verify related proteins.Results: In our study, BZXD ameliorated joint inflammation, suppressed the pathological changes in arthrosis of CIA rats. The proteomic analysis demonstrated that CIA rats were mainly involved in two significant pathways (the focal adhesion and the ECM-receptor interaction) in the early stage. BZXD down-regulated the expression of proteins involved in these pathways, such as CAV1, CHAD, COL3A1, COL5A2, COL6A1 and COL6A5. Additionally, BZXD exerts anti-inflammatory effects in the late stage mainly by increasing the expression of FASN, and affecting fatty acid metabolism.Conclusion: BZXD exerts therapeutic effects on RA through multi-pathways in the early and late stages. This work may provide proteomic clues for treating RA by BZXD.

scholarly journals Aqueous extract of Kan-Lu-Hsiao-Tu-Tan ameliorates collagen-induced arthritis in mice by regulating immune and inflammatory responses

2020 ◽  
Author(s):  
Chih-Chao Chiang ◽  
Yi‐Rong Li ◽  
Kuei-Hung Lai ◽  
Wei-Jen Cheng ◽  
Shih-Chao Lin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Peroxide ◽  
Th17 Cells ◽  
Inflammatory Responses ◽  
Bone Erosion ◽  
Cartilage Damage ◽  
Radical Scavenging ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Anti Inflammatory

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disease featured by joint inflammation and systemic comorbidities. Kan-Lu-Hsiao-Tu-Tan (KLHTT), a Chinese medicine formulation, has free radical scavenging capacity and anti-inflammatory activity in vitro. However, its anti-arthritic effect remains unknown. Herein, we aimed to explore the anti-arthritic effects of KLHTT on collagen-induced arthritis (CIA) in mice and investigate the underlying mechanisms. Methods KLHTT was extracted using boiling water. KLHTT (50 and 100 mg/kg) was fed orally for 21 days once a day on CIA in DBA/1J mice. The severity of CIA was evaluated by histological assessments. Levels of inflammatory cytokines, malondialdehyde (MDA), and hydrogen peroxide (H2O2) were measured using ELISA, thiobarbituric acid reactive substances, and hydrogen peroxide assay kits, respectively. Anti-collagen type II (CII) antibody was assayed by ELISA. Proliferation of splenocytes was tested using radioactive thymidine incorporation assay. Levels of Th1 and Th17 cells were obtained using flow cytometry. Results KLHTT significantly ameliorated paw edema and restored body weight in CIA mice. The synovitis, cartilage damage, and bone erosion were reduced by KLHTT. KLHTT exhibited anti-inflammatory effects by decreasing the levels of interleukin (IL)-1β, IL-6, IL-17A, and tumour necrosis factor-α in the paw homogenates and serum. KLHTT also showed antioxidant activity by reducing the concentrations of MDA and H2O2 in paw tissues. Moreover, KLHTT reduced anti-CII antibody formation, suppressed splenocyte proliferation, and mitigated the levels of splenic Th1 and Th17 cells in CIA mice. Conclusion The therapeutic effects of KLHTT in CIA mice were through regulating immune and inflammatory responses. Our results suggest that KLHTT has potential to treat rheumatoid arthritis.

scholarly journals SAT0007 BLOCKING HISTAMINE-RELEASING FACTOR/TRANSLATIONALLY CONTROLLED TUMOR PROTEIN (HRF/TCTP) ATTENUATES AGGRESSIVENESS OF FIBROBLAST-LIKE SYNOVIOCYTES AND AMELIORATES COLLAGEN-INDUCED ARTHRITIS IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 934.3-934
Author(s):  
M. Kim ◽  
Y. Choe ◽  
H. Lee ◽  
Y. H. Cheon ◽  
S. I. Lee
Keyword(s):  
Rheumatoid Arthritis ◽  
Cancer Progression ◽  
Inflammatory Responses ◽  
Joint Destruction ◽  
Serum Levels ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Translationally Controlled Tumor Protein ◽  
Biochemical Analyses ◽  
Fibroblast Like Synoviocytes

Background:Histamine-releasing factor/translationally controlled tumor protein (HRF/TCTP) stimulates cancer progression and allergic responses. Increased expression of HRF/TCTP occurs in joints of rheumatoid arthritis (RA) patients, but the role of HRF/TCTP in RA remains undefinedObjectives:In this study, we explored the pathogenic significance of HRF/TCTP and evaluated therapeutic effects of HRF/TCTP blockade in RA.Methods:HRF/TCTP transgenic (TG) and knockdown (KD) mice with collagen-induced arthritis (CIA) were used to determine experimental phenotypes of RA. HRF/TCTP levels were measured in sera and joint fluids in patients with RA and compared to those with osteoarthritis, ankylosing spondylitis, Behcet disease, and healthy controls. HRF/TCTP expression was also assessed in synovium and fibroblast-like synoviocytes (FLS) obtained from RA or OA patients. Finally, we assessed effects of HRF/TCTP and dimerized HRF/TCTP binding peptide-2 (dTBP2), an inhibitor of HRF/TCTP, in RA-FLS and CIA mice.Results:Our clinical, radiological, histological, and biochemical analyses indicate that inflammatory responses and joint destruction were increased in HRF/TCTP TG mice, and decreased in KD mice compared to wild-type littermates. HRF/TCTP levels were higher in sera, synovial fluid, synovium, and FLS of patients with RA than in control groups. Serum levels of HRF/TCTP correlated well with disease activity in RA. Tumor-like aggressiveness of RA-FLS was exacerbated by HRF/TCTP stimulation and ameliorated by dTBP2 treatment. dTBP2 exerted protective and therapeutic effects in CIA mice, and had no detrimental effect in a murine tuberculosis model.Conclusion:Our results indicate that HRF/TCTP represents a novel biomarker and therapeutic target for diagnosis and treatment of RA.References:N/AAcknowledgments :National Research Foundation of KoreaKorea Health Industry Development InstituteDisclosure of Interests:None declared

scholarly journals AB0043 EFFECT OF ANTI-INFLAMMATORY MEDICATION ON INTERACTION OF SYNOVIAL FIBROBLASTS WITH MACROPHAGES IN RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1054.1-1054
Author(s):  
M. Schmeller ◽  
M. Diller ◽  
R. Hasseli ◽  
A. Knothe ◽  
S. Rehart ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mononuclear Cells ◽  
Joint Inflammation ◽  
Synovial Fibroblasts ◽  
Therapeutic Effects ◽  
Synergistic Activity ◽  
M1 Macrophages ◽  
Healthy Donors ◽  
Proinflammatory Activity ◽  
Anti Inflammatory

Background:One of the key mechanisms in the pathogenesis of rheumatoid arthritis (RA) is the interaction of macrophages and synovial fibroblasts during joint inflammation. Increased synergistic proinflammatory activity of both cell types leads to the release of high levels of proinflammatory cytokines, especially of interleukin-6 (IL-6), and of matrix degrading enzymes. If this mechanism is uncontrolled, progressive destruction of articular cartilage and bone will take place.In active disease, immediate anti-inflammatory treatment with glucocorticoids is usually replaced by disease-modifying anti-rheumatic drugs (DMARDS), especially by methotrexate (MTX) and biologics such as TNF-α- or IL-6-inhibitors. This led to great improvements in prognosis and outcome for RA patients. However, about 40% of patients experience no remission or suffer from side effects of medication. To optimize established substances and to develop new treatment strategies, it is necessary to understand the mechanisms underlying the limited therapeutic effects.Objectives:Evaluation of the effect of prednisolone, MTX, adalimumab, tocilizumab on IL-6 secretion by RA synovial fibroblasts (RASF) and macrophages.Methods:RA synovium was used for RASF isolation. Peripheral blood mononuclear cells (PBMCs) were isolated from blood of healthy donors and RA patients by using Ficoll© medium followed by density gradient centrifugation. Mononuclear cells were seeded on six well plates (6x10^6/well) and incubated for one week. Then they were stimulated with Interferon-у (20 ng/ml) and LPS (50 ng/ml) for 48h to initiate differentiation into proinflammatory M1 macrophages. The M1 macrophages were co-cultured with RASF (100.000/well) and different treatments added (prednisolone: 10, 25, 50, 75, 100 nM, 1 µM; adalimumab: 100, 500 µg/ml; tocilizumab: 1, 5 µg/ml; MTX: 0,5, 1, 5, 10, 100 nM, 1µM). After 24h culture supernatants were collected and IL-6- and TNFα-ELISAs were performed.Results:IL-6 concentrations of untreated controls were comparable, regardless whether M1 macrophages from healthy donors or RA-patients were used for co-culture. Prednisolone reduced co-culture-induced IL-6 up to 56% (p<0.001) in co-culture of RASF and M1 macrophages of healthy donors and up to 60% (p<0.001) in co-culture of RASF and RA M1 macrophages. Adalimumab reduced IL-6 up to 28% (p<0.05) in M1 of healthy donors and up to 45% (p<0.01) in RA M1 macrophage co-cultures. A minor reduction by 10-20% of IL-6 was observed with tocilizumab and no significant effect could be achieved after treatment with MTX.Conclusion:Prednisolone and adalimumab clearly decrease but do not eliminate proinflammatory synergistic activity of RASF and M1 macrophages. These results confirm the clinical observation, that there is a large number of RA-patients that independent of anti-inflammatory treatment still suffer from low-level joint inflammation.The synergistic proinflammatory activity of M1 macrophages and RASF seems to be a complex and multifactorial mechanism that is difficult to eliminate by a single treatment substance. Since it is one of the key mechanisms in RA pathogenesis, there is a critical need to investigate how therapy effects could be optimized. This study confirmed RASFs as one of the leading effector cells of increased synergistic proinflammatory activity, thus underlining their promising role as a treatment target in rheumatoid arthritis.Disclosure of Interests:None declared

scholarly journals The Protective Effect of Yi Shen Juan Bi Pill in Arthritic Rats with Castration-Induced Kidney Deficiency

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Hongyan Zhao ◽  
Jian Li ◽  
Xiaojuan He ◽  
Cheng Lu ◽  
Cheng Xiao ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Protective Effect ◽  
Androgen Deficiency ◽  
Sprague Dawley ◽  
Collagen Induced Arthritis ◽  
Common Pattern ◽  
Pharmacological Mechanism ◽  
Kidney Deficiency ◽  
Sprague Dawley Rats ◽  
Lipid Metabolites

Androgens have been linked to the onset, severity, and progression of rheumatoid arthritis (RA). In traditional Chinese medicine (TCM), the most common pattern in RA is kidney deficiency, which partly corresponds to a low sex hormone state. In this study, TCM kidney deficiency was induced in male Sprague-Dawley rats with castration surgery, and a TCM preparation, Yi Shen Juan Bi Pill (YJB), was used to treat collagen induced arthritis (CIA) rats with castration. Metabolomic technique was used to evaluate the pharmacological mechanism in castrated CIA rats treated by YJB. The results showed that castration significantly increased the severity of the arthritis in rats but was ameliorated by YJB. Its pharmacological mechanism was partially associated with lipid metabolites involving free fatty acid (FFA) and lysophosphatidylcholine (LPC).In conclusion, the experimental results demonstrate the protective effect of YJB on the TCM kidney deficiency pattern induced by androgen deficiency in CIA rats and support that YJB should be used for the clinical treatment of RA with TCM kidney deficiency pattern.

scholarly journals Protective effects of agonists of growth hormone-releasing hormone (GHRH) in early experimental diabetic retinopathy

2017 ◽  
Vol 114 (50) ◽  
pp. 13248-13253 ◽  
Author(s):  
Menaka C. Thounaojam ◽  
Folami L. Powell ◽  
Sagar Patel ◽  
Diana R. Gutsaeva ◽  
Amany Tawfik ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Diabetic Retinopathy ◽  
Early Stage ◽  
Pigment Epithelium ◽  
Morphological Alteration ◽  
Retinal Layer ◽  
Therapeutic Effects ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Anti Inflammatory

The potential therapeutic effects of agonistic analogs of growth hormone-releasing hormone (GHRH) and their mechanism of action were investigated in diabetic retinopathy (DR). Streptozotocin-induced diabetic rats (STZ-rats) were treated with 15 μg/kg GHRH agonist, MR-409, or GHRH antagonist, MIA-602. At the end of treatment, morphological and biochemical analyses assessed the effects of these compounds on retinal neurovascular injury induced by hyperglycemia. The expression levels of GHRH and its receptor (GHRH-R) measured by qPCR and Western blotting were significantly down-regulated in retinas of STZ-rats and in human diabetic retinas (postmortem) compared with their respective controls. Treatment of STZ-rats with the GHRH agonist, MR-409, prevented retinal morphological alteration induced by hyperglycemia, particularly preserving survival of retinal ganglion cells. The reverse, using the GHRH antagonist, MIA-602, resulted in worsening of retinal morphology and a significant alteration of the outer retinal layer. Explaining these results, we have found that MR-409 exerted antioxidant and anti-inflammatory effects in retinas of the treated rats, as shown by up-regulation of NRF-2-dependent gene expression and down-regulation of proinflammatory cytokines and adhesion molecules. MR-409 also significantly down-regulated the expression of vascular endothelial growth factor while increasing that of pigment epithelium-derived factor in diabetic retinas. These effects correlated with decreased vascular permeability. In summary, our findings suggest a neurovascular protective effect of GHRH analogs during the early stage of diabetic retinopathy through their antioxidant and anti-inflammatory properties.

scholarly journals Sec-O-glucosylhamaudol suppressed inflammatory reaction induced by LPS in RAW264.7 cells through inhibition of NF-κB and MAPKs signaling

2020 ◽  
Vol 40 (2) ◽  
Author(s):  
Guiming Liu ◽  
Jing Xie ◽  
Yurui Shi ◽  
Rongda Chen ◽  
Li Li ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bioactive Compound ◽  
Therapeutic Effects ◽  
Raw 264.7 ◽  
Pcr Assay ◽  
Raw 264.7 Cell ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Saposhnikovia Divaricata ◽  
Inflammation Cytokines

Abstract As a major bioactive compound from the Saposhnikovia divaricata (Turcz.) Schischk, sec-O-glucosylhamaudol (SOG), has been reported to have anti-nociceptive activity and high 5-lipoxygenase (5-LOX) activity. Nevertheless, the mechanism of the potential anti-inflammatory effects of SOG is unclear. The anti-inflammatory impacts of SOG in RAW 264.7 cell lines stimulated by LPS were explored in the present study. It was found that SOG dose-dependently reduced the emergence of inflammation cytokines, such as IL-6 and TNF-α in Raw264.7 murine macrophages stimulated by LPS. Real-time PCR assay demonstrated the SOG dose-dependently inhibited transcription of these cytokines as well. In addition, it was also found that NF-κB activation and MAPKs phosphorylation including p38, JNK and ERK1/2 induced by LPS were suppressed by SOG. Due to its anti-inflammatory activity, our results suggest that SOG might have therapeutic effects on inflammatory disease, such as acute lung injury or rheumatoid arthritis.

scholarly journals Application of GC/MS-Based Metabonomic Profiling in Studying the Therapeutic Effects of Aconitum carmichaeli with Ampelopsis japonica Extract on Collagen-Induced Arthritis in Rats

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1934 ◽  
Author(s):  
Hua Jin ◽  
Ningning Ma ◽  
Xin Li ◽  
Mingqin Kang ◽  
Maojuan Guo ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mechanism Of Action ◽  
Inositol Phosphate ◽  
Support Vector ◽  
Therapeutic Effects ◽  
Collagen Induced Arthritis ◽  
Galactose Metabolism ◽  
Inositol Phosphate Metabolism ◽  
Therapeutic Mechanism ◽  
Aconitum Carmichaeli

Aconitum carmichaeli with Ampelopsis japonica (AA) is a classical traditional Chinese medicine (TCM) formula. There are a lot of examples showing that AA can be used to treat rheumatoid arthritis, but its mechanism of action is still not completely clear. In this research, collagen-induced arthritis (CIA) was chosen as a rheumatoid arthritis (RA) model. Rats of treated groups were continuously administered Aconitum carmichaeli (AC), Ampelopsis japonica (AJ) and Aconitum carmichaeli + Ampelopsis japonica (AA) orally once a day from the day after the onset of arthritis (day 7) until day 42. The results showed that AA not only significantly reduced paw swelling, but also improved the levels of TNF-α and IL-6 in serum. GC-MS-based urine metabonomics was established to analysis metabolic profiles and 21 biomarkers of RA rats were identified by the Partial Least Squares Discriminant Analysis (PLS-DA) and Support Vector Machine (SVM) methods. The prediction rate of the SVM method for the 21 biomarkers was 100%. Twenty of 21 biomarkers, including D-galactose, inositol and glycerol, gradually returned to normal levels after administration of AA. Metabolomic Pathway Analysis (MetPA) generated three related metabolic pathways—galactose metabolism, glycerolipid metabolism and inositol phosphate metabolism—which explain the mechanism of AA treatment of rheumatoid arthritis. This research provides a better understanding of the therapeutic effects and possible therapeutic mechanism of action of a complex TCM (AA) on rheumatoid arthritis.

Evaluation of Therapeutic Effects of Quercetin Against Achilles Tendinopathy in Rats via Oxidative Stress, Inflammation, Apoptosis, Autophagy, and Metalloproteinases

2021 ◽  
pp. 036354652110598
Author(s):  
Halil Sezgin Semis ◽  
Cihan Gur ◽  
Mustafa Ileriturk ◽  
Fatih Mehmet Kandemir ◽  
Ozgur Kaynar
Keyword(s):  
Oxidative Stress ◽  
Achilles Tendinopathy ◽  
Therapeutic Effects ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Alternative Treatment Option ◽  
Markers Of Oxidative Stress ◽  
Inflammatory Drugs ◽  
Anti Inflammatory ◽  
The One

Background: Achilles tendinopathy, seen in athletes and manual labor workers, is an inflammatory condition characterized by chronic tendon pain. Owing to the toxicity that develops in various organs attributed to the use of anti–inflammatory drugs, there is a need for new therapeutic agents. Purpose: In the present study, the effects of quercetin (Que), the one that attracted the most attention of researchers studying this group of flavonoids, were investigated against collagenase–induced tendinopathy. Study Design: Controlled laboratory study. Methods: A total of 35 Sprague-Dawley rats were used in the study. Tendinopathy was created by injecting a single dose of collagenase (10 μL; 10 mg/mL) into the tendons of rats. Thirty minutes after the injection, Que was administered at doses of 25 or 50 mg/kg. Que administration was carried out for 7 days. Animals underwent a motility test at the end of the study. In addition, markers of oxidative stress, inflammation, apoptosis, and autophagy, as well as the expression levels of matrix metalloproteinases (MMPs 2, 3, 9, and 13), ICAM-1, and STAT3, were measured in tendon tissues with biochemical, molecular, and Western blot techniques. Results: The results showed that oxidative stress, inflammation, apoptosis, and autophagy were triggered by the injection of collagenase. In addition, MMPs, ICAM-1, and STAT3 were activated to participate in the development of tendinopathy. Que was found to reduce ICAM-1 levels in tendon tissue. Moreover, Que showed antioxidant, anti–inflammatory, antiapoptotic, and antiautophagic effects on tendons against tendinopathy. More important, Que suppressed the expression of MMPs in the tendon tissues. Conclusion: Que has protective properties against collagenase–induced tendon damage in rats. Clinical Relevance: We believe that with further study, Que may be shown to be an alternative treatment option for athletes or others who experience tendon injuries.

Comparison of the Therapeutic Effects of Gold Nanoclusters and Gold Nanoparticles on Rheumatoid Arthritis

2019 ◽  
Vol 15 (11) ◽  
pp. 2281-2290 ◽  
Author(s):  
Yao Zhao ◽  
Zhesheng He ◽  
Ruoping Wang ◽  
Pengju Cai ◽  
Xiangchun Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Au Nanoparticles ◽  
Type Ii Collagen ◽  
Therapeutic Effects ◽  
Type Ii ◽  
Au Clusters ◽  
Anti Inflammatory ◽  
Inflammatory Effect

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive cartilage and bone damage. In our previous studies, we found that Au clusters using glutathione as a template (GACs) produced profound anti-inflammatory effects in vitro on lipopolysaccharide (LPS)-induced inflammation in mouse macrophage RAW 264.7 cells and type II collagen-induced rat RA in vivo. In this study, we examined whether the template for Au clusters synthesis has an effect on its anti-inflammatory effect and whether Au nanoparticles with larger particle diameter produce the same anti-inflammatory effect. We synthesized Au clusters with bovine serum albumin (BSA) as a template (BACs), Au clusters with glutathione (GSH) as a template (GACs), and Au nanoparticles with glutathione as a template (GANs) and compared their anti-inflammatory effects in vitro and in vivo. These three Au nanomaterials can inhibit the production of lipopolysaccharide (LPS)-induced proinflammatory mediators and ameliorate type II collagen-induced rat RA. However, although the three Au nanomaterials produced similar anti-inflammatory effects, the GANs with larger particle sizes were less stable in vivo and accumulated in the peritoneum after intraperitoneal injection, resulting in poor absorption in vivo. The BACs showed relatively high liver accumulation due to the larger molecular weight of the outer shell. Therefore, we believe that the GACs are potential reliable nanodrugs for the treatment of RA.

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.

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