scholarly journals Targeted apoptosis of macrophages and osteoclasts in arthritic joints is effective against advanced inflammatory arthritis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Caifeng Deng ◽  
Quan Zhang ◽  
Penghui He ◽  
Bin Zhou ◽  
Ke He ◽  
...  
Keyword(s):  
Inflammatory Arthritis ◽  
Bone Erosion ◽  
Joint Inflammation ◽  
Αvβ3 Integrin ◽  
Matrix Metalloprotease ◽  
Arthritic Joint ◽  
Specific Distribution ◽  
Induced Apoptosis ◽  
Inflammatory Macrophages ◽  
Arthritic Joints

AbstractInsufficient apoptosis of inflammatory macrophages and osteoclasts (OCs) in rheumatoid arthritis (RA) joints contributes toward the persistent progression of joint inflammation and destruction. Here, we deliver celastrol (CEL) to selectively induce apoptosis of OCs and macrophages in arthritic joints, with enzyme-responsive nanoparticles (termed PRNPs) composed of RGD modified nanoparticles (termed RNPs) covered with cleavable PEG chains. CEL-loaded PRNPs (CEL-PRNPs) dually target OCs and inflammatory macrophages derived from patients with RA via an RGD-αvβ3 integrin interaction after PEG cleavage by matrix metalloprotease 9, leading to increased apoptosis of these cells. In an adjuvant-induced arthritis rat model, PRNPs have an arthritic joint-specific distribution and CEL-PRNPs efficiently reduce the number of OCs and inflammatory macrophages within these joints. Additionally, rats with advanced arthritis go into inflammatory remission with bone erosion repair and negligible side effects after CEL-PRNPs treatment. These findings indicate potential for targeting chemotherapy-induced apoptosis in the treatment of advanced inflammatory arthritis.

scholarly journals The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis

2020 ◽  
Vol 99 (4) ◽  
pp. 456-462 ◽  
Author(s):  
E. Muñoz-Atienza ◽  
M.B. Flak ◽  
J. Sirr ◽  
N.A. Paramonov ◽  
J. Aduse-Opoku ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Arthritis ◽  
Strong Association ◽  
Intestinal Barrier ◽  
Joint Inflammation ◽  
Chronic Inflammatory Disease ◽  
Antibody Activity ◽  
Drug Naïve ◽  
Barrier Breakdown ◽  
Arthritic Joints

Rheumatoid arthritis (RA), a chronic inflammatory disease affecting primarily the joints, is frequently characterized by the presence of autoimmune anticitrullinated protein antibodies (ACPA) during preclinical stages of disease and accumulation of hypercitrullinated proteins in arthritic joints. A strong association has been reported between RA and periodontal disease, and Porphyromonas gingivalis, a known driver of periodontitis, has been proposed as the microbial link underlying this association. We recently demonstrated P. gingivalis–mediated gut barrier breakdown and exacerbation of joint inflammation during inflammatory arthritis. In the present study, we investigated another potential role for P. gingivalis in RA etiopathogenesis, based on the generation of ACPA through the activity of a unique P. gingivalis peptidylarginine deiminase (PPAD) produced by this bacterium, which is capable of protein citrullination. Using a novel P. gingivalis W50 PPAD mutant strain, incapable of protein citrullination, and serum from disease-modifying antirheumatic drug–naïve early arthritis patients, we assessed whether autocitrullinated proteins in the P. gingivalis proteome serve as cross-activation targets in the initiation of ACPA production. We found no evidence for patient antibody activity specific to autocitrullinated P. gingivalis proteins. Moreover, deletion of PPAD did not prevent P. gingivalis–mediated intestinal barrier breakdown and exacerbation of disease during inflammatory arthritis in a murine model. Together, these findings suggest that the enzymatic activity of PPAD is not a major virulence mechanism during early stages of inflammatory arthritis.

scholarly journals OP0182 PROTEOGLYCAN LOSS IN ARTICULAR CARTILAGE IS ASSOCIATED WITH JOINT INFLAMMATION SEVERITY IN PSORIATIC ARTHRITIS – A COMPOSITIONAL MAGNETIC RESONANCE IMAGING STUDY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 113.2-113
Author(s):  
P. Sewerin ◽  
D. Abrar ◽  
S. Nebelung ◽  
M. Frenken ◽  
T. Ulrich ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Bone Erosion ◽  
Joint Inflammation ◽  
Resonance Imaging ◽  
Research Support ◽  
Weighted Image ◽  
The Third ◽  
Deutschland Gmbh ◽  
Pip Joint ◽  
Flexor Tenosynovitis

Background:Even though cartilage loss is a known feature of psoriatic arthritis (PsA), little is known about its role in the pathogenesis of PsA. Using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) as a non-invasive marker of the tissue’s proteoglycan content, such early (i.e. pre-morphological) changes have been associated with inflammation in rheumatoid arthritis (RA). Yet, this association has not been studied before in PsA.Objectives:Is the severity of local joint inflammation associated to local proteoglycan loss in PsA patients?Methods:Metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints of 17 patients with active PsA were evaluated by high-resolution clinical standard morphological and dGEMRIC sequences using a 3T MRI scanner (Magnetom Skyra, Siemens) and a dedicated 16-channel hand coil. Images were analyzed by two independent raters for dGEMRIC indices, PsA MRI scores (PsAMRIS) and total cartilage thickness (TCT). Kendall-Tau correlation coefficients (τ) were calculated.Results:We found significant negative correlations between dGEMRIC indices and total PsAMRIS (τ = -0.5, p= 0.012), synovitis (τ = -0.56, p= 0.006), flexor tenosynovitis (τ = -0.4, p= 0.049), and periarticular inflammation (τ = -0.72, p< 0.001). Significant positive correlations were found between TCT and dGEMRIC indices in all joint levels (τ = 0.43, p<0.001). No significant correlations were determined between dGEMRIC indices and bone erosion, bone edema or bone proliferation.Conclusion:In PsA, proteoglycan loss as assessed by dGEMRIC is associated with periarticular inflammation, synovitis, and flexor tenosynovitis, but not with bone erosion or proliferation, thereby highlighting the need for effective anti-inflammatory treatment regimes. Beyond morphology, advanced MRI techniques may be used to assess cartilage composition in PsA and to identify early changes in cartilage as an imaging biomarker with potential application in detection and monitoring of PsA.Figure 1Right hand of a 26-year-old male with psoriatic arthritis Coronal STIR image (A) of digits 1-5, transversal fat-saturated (fs) T2-weighted image of digits 2-4 (B) and the corresponding transversal fs contrast-enhanced T1-weighted image (C) at the distal portion of the proximal phalanges. Horizontal white bar in (A) indicates level of transversal slices (B) & (C). Sagittal fs Proton Density-weighted image of the third digit (D). A: Increased signal at the collateral ligaments and synovitis of the proximal interphalangeal (PIP) joint of the third digit (white arrow). Periarticular inflammation around the PIP joint and the body of the proximal phalanx of the third digit (arrowhead). B & C: Extensive flexor tenosynovitis (asterix) and periarticular inflammation in the subcutaneous tissues (arrowhead) alongside thickened flexor tendon pulleys (arrow). D & E: Representative sagittal T1-weighted images of the MCP, PIP and DIP joint of the 3rd digit. Following iv contrast administration and appropriate delay of 40 min, A gives the morphological T1 map, while B gives the corresponding parameter map with dGEMRIC values [ms] overlaid. Note the significant decrease in dGEMRIC indices of the PIP joint as compared to the MCP joint.Disclosure of Interests:Philipp Sewerin Grant/research support from: AbbVie Deutschland GmbH & Co. KGBristol-Myers Squibb Celgene GmbHLilly Deutschland GmbHNovartis Pharma GmbH Pfizer Deutschland GmbHRheumazentrum Rhein-Ruhr, Consultant of: AMGEN GmbH AbbVie Deutschland GmbH & Co. KG Biogen GmbHBristol-Myers Squibb Celgene GmbH Chugai Pharma arketing Ltd. / Chugai Europe GmbHHexal Pharma Janssen-CilagGmbH Johnson & Johnson Deutschland GmbHLilly Deutschland GmbH / Lilly Europe / Lilly Global Novartis Pharma GmbH Pfizer Deutschland GmbH Roche Pharma Rheumazentrum Rhein-Ruhr Sanofi-Genzyme Deutschland GmbH Swedish Orphan Biovitrum GmbH UCB Pharma GmbH, Speakers bureau: AMGEN GmbH AbbVie Deutschland GmbH & Co. KG Biogen GmbHBristol-Myers Squibb Celgene GmbH Chugai Pharma arketing Ltd. / Chugai Europe GmbHHexal Pharma Janssen-CilagGmbH Johnson & Johnson Deutschland GmbHLilly Deutschland GmbH / Lilly Europe / Lilly Global Novartis Pharma GmbH Pfizer Deutschland GmbH Roche Pharma Rheumazentrum Rhein-Ruhr Sanofi-Genzyme Deutschland GmbH Swedish Orphan Biovitrum GmbH UCB Pharma GmbH, Daniel Abrar: None declared, Sven Nebelung: None declared, Miriam Frenken: None declared, Tim Ulrich: None declared, Karl Ludger Radke: None declared, Gerald Antoch: None declared, Stefan Vordenbäumen: None declared, Ralph Brinks: None declared, Matthias Schneider Grant/research support from: GSK, UCB, Abbvie, Consultant of: Abbvie, Alexion, Astra Zeneca, BMS, Boehringer Ingelheim, Gilead, Lilly, Sanofi, UCB, Speakers bureau: Abbvie, Astra Zeneca, BMS, Chugai, GSK, Lilly, Pfizer, Sanofi, Benedikt Ostendorf: None declared, Christoph Schleich: None declared

scholarly journals Intracellular versus extracellular inhibition of calpain I causes differential effects on pain in a rat model of joint inflammation

2021 ◽  
Vol 17 ◽  
pp. 174480692110161
Author(s):  
Jason J McDougall ◽  
Miranda McConnell ◽  
Allison R Reid
Keyword(s):  
Joint Pain ◽  
Acute Inflammation ◽  
Weight Bearing ◽  
Joint Inflammation ◽  
Local Administration ◽  
Calpain Inhibitor ◽  
Mast Cell Tryptase ◽  
Calcium Dependent ◽  
Protease Activated Receptor 2 ◽  
Arthritic Joints

Calpain I is a calcium-dependent cysteine protease which has dual effects on tissue inflammation depending on its cellular location. Intracellularly, calpain I has pro-inflammatory properties but becomes anti-inflammatory when exteriorised into the extracellular space. In this study, the effect of calpain I on joint pain was investigated using the kaolin/carrageenan model of acute synovitis. Evoked pain behaviour was determined by von Frey hair algesiometry and non-evoked pain was measured using dynamic hindlimb weight bearing. Local administration of calpain I reduced secondary allodynia in the acute inflammation model and this effect was blocked by the cell impermeable calpain inhibitor E-64c. Calpain I also blocked the algesic effect of the protease activated receptor-2 (PAR-2) cleaving enzyme mast cell tryptase. The cell permeable calpain blocker E-64d also produced analgesia in arthritic joints. These data suggest that calpain I produces disparate effects on joint pain viz. analgesia when present extracellularly by disarming PAR-2, and pro-algesic when the enzyme is inside the cell.

scholarly journals ZhiJingSan Inhibits Osteoclastogenesis via Regulating RANKL/NF-κB Signaling Pathway and Ameliorates Bone Erosion in Collagen-Induced Mouse Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Ling ◽  
Jie Yang ◽  
Di Hua ◽  
Dawei Wang ◽  
Chenglei Zhao ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Bone Erosion ◽  
Cell Model ◽  
Pathological Condition ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Joint Inflammation ◽  
Underlying Mechanism ◽  
Bovine Collagen

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch, scolopendridae) and scorpion (dried body of Buthus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigated in vitro in an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin K in vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.

Orally administered antigen can reduce or exacerbate pathology in an animal model of inflammatory arthritis dependent upon the timing of administration

2022 ◽  
Author(s):  
Gavin Robertson Meehan ◽  
Iain B McInnes ◽  
James M Brewer ◽  
Paul Garside
Keyword(s):  
Inflammatory Arthritis ◽  
Opposite Effect ◽  
Short Communication ◽  
Serum Antibody ◽  
Joint Inflammation ◽  
Disease Symptoms ◽  
Considerable Research ◽  
Self Tolerance ◽  
The Impact ◽  
Specific Tolerance

Currently, treatments for rheumatoid arthritis (RA) are focussed on treatment of disease symptoms rather than addressing the cause of disease, which could lead to remission and cure. Central to disease development is the induction of autoimmunity through a breach of self-tolerance. There is considerable research in RA focussed on antigens and approaches to re-establish antigen specific tolerance. A crucial step in this research is to employ appropriate animal models to test prospective antigen specific immunotherapies, preferably in the context of joint inflammation. In this short communication, we use our previously developed model of antigen specific inflammatory arthritis in which OVA-specific TcR tg T cells drive breach of tolerance to endogenous antigens to determine the impact that the timing of therapy administration has upon disease progression. Using antigen feeding to induce tolerance we demonstrate that administration prior to articular challenge results in a reduced disease score as evidenced by pathology and serum antibody responses. By contrast, feeding antigen after articular challenge had the opposite effect and resulted in the exacerbation of pathology. Although preliminary, these data suggest that the timing of antigen administration may be key to the success of tolerogenic immunotherapies. This has important implications for the timing of potential tolerogenic therapies in patients.

IRAK4 inhibition: a promising strategy for treating RA joint inflammation and bone erosion

2020 ◽  
Author(s):  
Sadiq Umar ◽  
Karol Palasiewicz ◽  
Katrien Van Raemdonck ◽  
Michael V. Volin ◽  
Bianca Romay ◽  
...  
Keyword(s):  
Bone Erosion ◽  
Joint Inflammation ◽  
Promising Strategy

scholarly journals TNFα depleting therapy improves fertility and animal welfare in TNFα-driven transgenic models of polyarthritis when administered in their routine breeding

2017 ◽  
Vol 52 (1) ◽  
pp. 59-68 ◽  
Author(s):  
Amy J. Naylor ◽  
Guillaume Desanti ◽  
Atif N. Saghir ◽  
Rowan S. Hardy
Keyword(s):  
Animal Welfare ◽  
Bone Erosion ◽  
Joint Destruction ◽  
Joint Inflammation ◽  
Micro Computed Tomography ◽  
Necrosis Factor Alpha ◽  
Clinical Scores ◽  
Breeding Management ◽  
Factor Alpha ◽  
Breeding Groups

Transgenic tumour necrosis factor alpha (TNFα)-driven models of polyarthritis such as the TNFΔARE mouse have proven to be invaluable in delineating aspects of inflammatory disease pathophysiology in humans. Unfortunately, the onset of joint destruction and inflammation in these models represents a significant detriment to breeding management. We examined whether TNFα depleting therapy ‘infliximab’ might represent a significant refinement in routine breeding. Clinical scores of joint inflammation were assessed in TNFΔARE males receiving either infliximab (10 mg/kg) or saline by twice-weekly intraperitoneal injection. Joint histology and bone morphology were assessed by histological analysis and micro-computed tomography (CT), respectively. Analysis of breeding was examined retrospectively in TNFΔARE males prior to, and following, regular introduction of infliximab. Clinical scores of inflammation were significantly reduced in TNFΔARE males receiving infliximab (control 6.6 arbitrary units [AU] ± 0.88 versus infliximab 4.4 AU ± 1.4; P < 0.05), while measures of pannus invasion and bone erosion by histology and micro-CT were markedly reduced. In the breeding groups, TNFΔARE males receiving infliximab injections sired more litters over their breeding lifespan (control 1.69 ± 0.22 versus infliximab 3.00 ± 0.19; P < 0.005). Furthermore, prior to infliximab, TNFΔARE males had a 26% risk of failing to sire any litters. This was reduced to 7% after the introduction of infliximab. This study is the first to report that regular administration of infliximab is effective at suppressing disease activity and improving animal welfare in TNFΔARE animals. In addition, we have shown that infliximab is highly efficacious in improving breeding behaviour and increasing the number of litters sired by TNFΔARE males.

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