Experimental Model Of Rheumatoid Arthritis Research Articles

Tetraspanin32 (TSPAN32) is downregulated in rheumatoid arthritis: Evidence from animal models and patients.

This study aimed to investigate the role of TSPAN32, a member of the tetraspanin family, in rheumatoid arthritis (RA). The objective was to assess the expression levels of TSPAN32 in experimental RA models and in RA patient immune cells, exploring its potential as a regulatory factor in RA pathogenesis. The study employed adjuvant-induced arthritis in rats and collagen-induced arthritis (CIA) in mice as experimental models. Exvivo analyses included evaluating TSPAN32 expression in immune cells at different stages of the disease. In silico data analysis involved examining transcriptomic datasets from drug-naïve and treated RA patients to correlate TSPAN32 expression with clinical parameters. TSPAN32 overexpression experiments in splenocytes from CIA mice aimed to demonstrate its functional impact on antigen-specific immune responses. The animal models revealed a significant downregulation of TSPAN32, particularly in synovial-infiltrating T cells. Also, TSPAN32 overexpression inhibited pro-inflammatory cytokine production in splenocytes. In RA patients, TSPAN32 was consistently downregulated in circulating and synovial-infiltrating T cells, as well as in CD8+ T cells, B cells and NK cells. Drug treatment did not significantly alter TSPAN32 levels. Negative correlations were observed between TSPAN32 expression and inflammatory markers (CRP, ESR) and clinical scores (SDAI) in RA patients. This study suggests that reduced TSPAN32 expression characterizes pathogenic T-cell populations in RA, highlighting its potential as biomarker for inflammation and disease activity. TSPAN32 may play a crucial role in shaping adaptive immune responses in RA, opening avenues for novel therapeutic strategies targeting this tetraspanin family member.

Comparison of disease-modifying anti-rheumatic drugs and hyperbaric oxygen therapy in the experimental model of rheumatoid arthritis in rats.

In this study, we wanted to investigate the effectiveness of combining disease-modifying anti-rheumatic drugs (DMARD) with hyperbaric oxygen therapy (HBOT) in reducing inflammation in a rheumatoid arthritis (RA) model using rats. We divided 56 male Sprague-Dawley rats into seven groups and induced RA using complete Freund's adjuvant. Some groups received HBOT, whereas others were given etanercept or leflunomide. We started the treatment on the 10th day after inducing RA and continued it for 18 days. To evaluate the effectiveness of the treatments, we measured paw swelling and used X-rays to examine the joints before and after the treatment. We also analysed the levels of two inflammatory markers, tumour necrosis factor (TNF)-α and interleukin (IL)-1β, using an enzyme-linked immunosorbent assay. Additionally, we conducted histological analysis and assessed the expressions of anti-IL-1β and anti-TNF-α antibodies. All the treatment groups showed a significant decrease in arthritis scores, paw swelling and levels of TNF-α and IL-1β. The X-ray images revealed improvements in joint structure, and the histopathological analysis showed reduced inflammation and collagen abnormalities. Combining DMARD with HBOT had similar effects to individual therapies, suggesting a cost-effective and potentially safer approach for improving outcomes in rats with RA.

Drug Targeting and Nanotherapeutic Advancement in the Treatment of Rheumatoid Arthritis: Recent Progress in Drug Delivery Systems.

Pain and swelling in the joints, increased synovial thickness, and bone and cartilage degeneration are all symptoms of Rheumatoid Arthritis (RA). Anti-rheumatic medications, which are used in conventional treatment plans for RA, need high doses, frequent administration, and long-term use, all of which increase the risk of major adverse effects and low patient compliance. Drug Delivery Systems (DDS) have been developed for RA treatment in an effort to avoid these obstacles and improve clinical efficacy. There have been many successful experimental RA models using these techniques. There has been a notable uptick in the study of RA nanotherapies as a prospective improvement over conventional systemic therapy. In order to overcome the limits of traditional treatments, researchers have begun looking into nanotherapeutic approaches, notably drug-delivery nanosystems. The precise delivery and concentration of therapeutic drugs in the affected regions are made possible by the passive or active targeting of systemic administration. Several new DDS for treating RA have been addressed here. Therefore, nanoscale drug delivery devices increase drug solubility and bioavailability while decreasing the need for higher doses.

MiRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Mechanistic insights into anti-inflammatory and immunosuppressive effects of plant secondary metabolites and their therapeutic potential for rheumatoid arthritis.

The anti-inflammatory and immunosuppressive activities of plant secondary metabolites are due to their diverse mechanisms of action against multifarious molecular targets such as modulation of the complex immune system associated with rheumatoid arthritis (RA). This review discussed and critically analyzed the potent anti-inflammatory and immunosuppressive effects of several phytochemicals and their underlying mechanisms in association with RA in experimental studies, including preliminary clinical studies of some of them. A wide range of phytochemicals including phenols, flavonoids, chalcones, xanthones, terpenoids, alkaloids, and glycosides have shown significant immunosuppressive and anti-inflammatory activities in experimental RA models and a few have undergone clinical trials for their efficacy and safety in reducing RA symptoms and improve patient outcomes. These phytochemicals have potential as safer alternatives to the existing drugs in the management of RA, which possess a wide range of serious side effects. Sufficient preclinical studies on safety and efficacy of these phytochemicals must be performed prior to proper clinical studies. Further studies are needed to address the barriers that have so far limited their human use before the therapeutic potential of these plant-based chemicals as anti-arthritic agents in the treatment of RA is fully realized.

NCF4 regulates antigen presentation of cysteine peptides by intracellular oxidative response and restricts activation of autoreactive and arthritogenic T cells

Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematous, are regulated by polymorphisms in genes contributing to the NOX2 complex. Mutations in both Ncf1 and Ncf4 affect development of arthritis in experimental models of RA, but the different regulatory pathways mediated by NOX2-derived reactive oxygen species (ROS) have not yet been clarified.Here we address the possibility that intracellular ROS, regulated by the NCF4 protein (earlier often denoted p40phox) which interacts with endosomal membranes, could play an important role in the oxidation of cysteine peptides in mononuclear phagocytic cells, thereby regulating antigen presentation and activation of arthritogenic T cells.To study the role of NCF4 we used mice with an amino acid replacing mutation (NCF4R58A), which is known to affect interaction with endosomal membranes, leading to decreased intracellular ROS production. To study the impact of NCF4 on T cell activation, we used the glucose phosphate isomerase peptide GPI325-339, which contains two cysteine residues (325-339c-c). Macrophages from mice with the NCF458A mutation efficiently presented the peptide when the two cysteines were intact and not crosslinked, leading to a strong arthritogenic T cell response. T cell priming occurred in the draining lymph nodes (LNs) within 8 days after immunization. Clodronate treatment, which depletes antigen-presenting mononuclear phagocytes, ameliorated arthritis severity, whereas treatment with FYT720, which traps activated T cells in LNs, prohibited arthritis.We conclude that NCF4-dependent intracellular ROS maintains cysteine peptides in an oxidized crosslinked state, which prevents presentation of peptides recognized by non-tolerized T cells and thereby protects against autoimmune arthritis.

Anti-inflammatory and antiresorptive effects of acyl substitution chromone derivatives in experimental model of rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting mainly small and major joints. The development for new drugs for the treatment of RAs is constantly underway, while the purposeful synthesis of multi-targeted small molecules can be considered a promising direction for the synthesis of new anti-rheumatic drugs.The aim. To evaluate the anti-inflammatory and antiresorptive effects of acyl substituted chromone derivatives in experimental animal model for rheumatoid arthritis.Materials and methods. RА was modeled in rats by injection of a suspension of human type II collagen and a complete Freunds adjuvant (in a ratio of 1:1) under plantar aponeurosis of the hind limb of the animal. The analyzed substances under ciphers X3A7 and X3A9 at a dose of 20 mg/kg and the reference drug dexamethasone at a dose of 3 mg/kg were administered intraperitoneally for 28 days from the moment of RA modeling. On the 7th, 14th, 21st and 28th days of the experiment, the severity of the clinical manifestations of RA was determined. After 28 days, changes in the content of cytokines in the rats blood serum were assessed: tumor necrosis factor-α (TNF-α), interleukins (IL-1, IL-6, IL-10 and IL-12). Changes of myeloperoxidase activity and concentrations of matrix metalloproteinases (MMPs) of type 2 and 9 were determined in synovial tissues.Results. During the study, it was shown that the use of the tested compounds X3A7 and X3A9, as well as the reference, contributed to a decrease in the severity of clinical manifestations of RA, starting from the 14th day of the experiment. Subsequently, it was demonstrated that in animals treated with dexamethasone, the cytokine content in blood serum decreased in relation to untreated animals: TNF-α – by 57.8% (p <0.05), IL-1 – 64.1% (p <0.05), IL-6 – 59.1% (p <0.05) and IL-12 – 72.3% (p <0.05), with an increase in the level of IL-10 – by 75.4% (p <0.05). The cytokine profile of the blood serum changed similarly when the studied compounds were administered to animals. It worth be noting that against the background of the administration of dexamethasone, X3A7 and X3A9 substances, the activity of myeloperoxidase decreased by 41.7 (p <0.05), 61.7 (p <0.05) and 65.0% (p <0.05), respectively, while the concentration of MMP2 decreased by 24.0 (p <0.05), 38.5 (p <0.05) and 34.4% (p <0.05), respectively, and MMP9 – by 13.5 (p <0.05), 37.9 (p <0.05) and 35.6% (p <0.05).Conclusion. The study showed that the administration of the analyzed chromone derivatives X3A7 and X3A9 suppresses inflammatory reactions and resorptive processes in synovial tissues, which can serve as a basis for their further study as antirheumatic agents.

Effects of Tofacitinib on Muscle Remodeling in Experimental Rheumatoid Sarcopenia.

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.

Protective and Pain-Killer Effects of AMC3, a Novel N-Formyl Peptide Receptors (FPRs) Modulator, in Experimental Models of Rheumatoid Arthritis.

Rheumatoid arthritis is an autoimmune disorder that causes chronic joint pain, swelling, and movement impairment, resulting from prolonged inflammation-induced cartilage and bone degradation. The pathogenesis of RA, which is still unclear, makes diagnosis and treatment difficult and calls for new therapeutic strategies to cure the disease. Recent research has identified FPRs as a promising druggable target, with AMC3, a novel agonist, showing preclinical efficacy in vitro and in vivo. In vitro, AMC3 (1-30 µM) exhibited significant antioxidant effects in IL-1β (10 ng/mL)-treated chondrocytes for 24 h. AMC3 displayed a protective effect by downregulating the mRNA expression of several pro-inflammatory and pro-algic genes (iNOS, COX-2, and VEGF-A), while upregulating genes essential for structural integrity (MMP-13, ADAMTS-4, and COLIAI). In vivo, AMC3 (10 mg kg-1) prevented hypersensitivity and restored postural balance in CFA-injected rats after 14 days. AMC3 attenuated joint alterations, reduced joint inflammatory infiltrate, pannus formation, and cartilage erosion. Chronic AMC3 administration reduced transcriptional changes of genes causing excitotoxicity and pain (EAATs and CCL2) and prevented morphological changes in astrocytes, including cell body hypertrophy, processes length, and thickness, caused by CFA in the spinal cord. This study demonstrates the usefulness of AMC3 and establishes the groundwork for further research.

Immunomodulatory Effects of Combined Nicotinic Acid and Prednisolone in Adjuvant-induced Arthritis.

The combination of two drugs may lead to better results while reducing the need for each medication. This study aimed to explore the synergistic benefits of combination therapy by suboptimal dose of niacin (Nic.) and prednisolone (Pred.) in an experimental model of Rheumatoid arthritis (RA). About 50 male Wistar rats (weighing 150 - 160 grams) were randomly divided into five groups of ten, including healthy and RA groups treated with Nic. (80 mg/kg-orally), or Pred. (2 mg/kg-orally), and/or co-administration of Nic. and Pred. (half doses with each one-orally). RA was induced by the injection of complete Freund's adjuvant into the hind paw of each rat. All treatments were initiated on the fifth day following the induction and continued until day 30 post-induction. The combined Nic. and Pred. at half doses promoted a significant regression in the severity of the established RA, which is more pronounced than full doses of either drug alone. Combination therapy promoted a reduction in some hematological and biochemical RA parameters, like neutral red uptake by phagocytic cells, myeloperoxidase, nitric oxide, and C-reactive protein, more profound than each drug alone. Combined treatment caused a greater decrease in IFN-γ expression than other treatments in the area of plantar joints. All treatments were effective in increasing the expression of the IL-10 in the area of plantar joints. Prednisolone was less effective in reducing the expression of the TNF-α in the area of plantar joints than the other group. This combination may be a useful approach to controlling RA.

Impacts of Valproic Acid on Systemic Bone Loss Associated with Experimental Model of Rheumatoid Arthritis in Rats

Background: Valproic acid (VA) is a compound used for many neurological disorders, which is also known as a histone deacetylase inhibitor. The impacts of VA on adjuvant-induced arthritis (AIA) in rats were investigated. Objectives: To investigate the possible osteoprotective and anti-inflammatory effects of VA in rheumatoid arthritis (RA). Materials and Methods: AIA was achieved through subdermal injection of complete Freund’s adjuvant (CFA) into the rat hindpaw. Forty Swiss albino rats were recruited in this study. These rats were divided into four groups: the normal control group received 0.1 mL phosphate buffer saline intraperitoneally each day, the positive control group received 0.75 mg/kg intraperitoneal once weekly dose of methotrexate, the AIA group received CFA without treatment, and the VA group received 300 mg/kg/day intraperitoneal dose of VA. Statistical analysis was done, and a P value of less than 0.05 was considered as statistically significant. Results: VA (300 mg/kg body weight) administered intraperitoneally could significantly reverse the effect of adjuvant arthritis on bone mineral density and bone mineral content in addition to an improvement in bone formation markers (osteoprotegerin, osteoprotegerin/RANKL ratio). Serum levels of tumor necrosis factor and interleukin 1b were significantly reduced by VA treatment. Reduced serum malondialdehyde with the elevated superoxide dismutase level was also achieved. Conclusion: These findings support the evidence that VA has a positive effect on bone anabolism and its anti-inflammatory properties could be considered as a bonus in inflammatory disorders induced bone loss such as RA.

Fluorinated polyamidoamine dendrimer-mediated miR-23b delivery for the treatment of experimental rheumatoid arthritis in rats

In rheumatoid arthritis (RA), insufficient apoptosis of macrophages and excessive generation of pro-inflammatory cytokines are intimately connected, accelerating the development of disease. Here, a fluorinated polyamidoamine dendrimer (FP) is used to deliver miR-23b to reduce inflammation by triggering the apoptosis of as well as inhibiting the inflammatory response in macrophages. Following the intravenous injection of FP/miR-23b nanoparticles in experimental RA models, the nanoparticles show therapeutic efficacy with inhibition of inflammatory response, reduced bone and cartilage erosion, suppression of synoviocyte infiltration and the recovery of mobility. Moreover, the nanoparticles accumulate in the inflamed joint and are non-specifically captured by synoviocytes, leading to the restoration of miR-23b expression in the synovium. The miR-23b nanoparticles target Tab2, Tab3 and Ikka to regulate the activation of NF-κB pathway in the hyperplastic synovium, thereby promoting anti-inflammatory and anti-proliferative responses. Additionally, the intravenous administration of FP/miR-23b nanoparticles do not induce obvious systemic toxicity. Overall, our work demonstrates that the combination of apoptosis induction and inflammatory inhibition could be a promising approach in the treatment of RA and possibly other autoimmune diseases.

Advances in experimental models of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by persistent articular inflammation and joint damage. RA was first described over 200 years ago; however, its etiology and pathophysiology remain insufficiently understood. The current treatment of RA is mainly empirical or based on the current understanding of etiology with limited efficacy and/or substantial side effects. Thus, the development of safer and more potent therapeutics, validated and optimized in experimental models, is urgently required. To improve the transition from bench to bedside, researchers must carefully select the appropriate experimental models as well as draw the right conclusions. Here, we summarize the establishment, pathological features, potential mechanisms, advantages, and limitations of the currently available RA models. The aim of the review is to help researchers better understand available RA models; discuss future trends in RA model development, which can help highlight new translational and human-based avenues in RA research.

Caffeic Acid Modified Nanomicelles Inhibit Articular Cartilage Deterioration and Reduce Disease Severity in Experimental Inflammatory Arthritis.

Inflammation plays an important role in the development of rheumatoid arthritis (RA). NR4A1 is an anti-inflammatory orphan nuclear receptor involved in protection from inflammatory stimuli in RA. In this study we have explored the anti-inflammatory potential of the FDA-approved drug 9-aminoacridine (9AA) and the natural compound caffeic acid (CA) conjugated to nanomicelles for the treatment of RA. We have synthesized methoxy polyethylene glycol polycaprolactone block copolymer (mPEG-b-PCL) by ring opening polymerization of ε-caprolactone. Then, we conjugated the hydrophilic caffeic acid (CA) with mPEG-b-PCL micelles via Steglich esterification and incorporated the 9AA drug. These nanomicelles were formulated by the solvent evaporation method with a size distribution around 190 nm and showed maximum drug loading capacity along with sustained drug release behavior. Furthermore, we tested the therapeutic potential of the formulated 9AA-encapsulated CA-conjugated nanomicelles (9AA-NMs) against an experimental RA model. We observed promising results which showed alleviation of arthritic symptoms by reducing inflammation, joint damage, bone erosion, and swelling. Further, collagen destruction was significantly reduced in articular cartilage, as shown by safranin-O and toluidine blue staining. The protective mechanism might be due to the simultaneous inhibition of NF-κB by 9AA and CA, whereas the activation of NR4A1 by 9AA leads to the suppression of HIF-1α. This combined therapeutic effect of 9AA and CA has enhanced the therapeutic efficacy of 9AA-NM and markedly reduced the severity of inflammatory arthritis. Unlike existing drugs for pain management and with limited efficacy, 9AA-NM exerted a disease-relevant activation/blockade that alleviated inflammation and exhibited marked therapeutic efficacy against RA.

Assessment of mesenchymal stem/stromal cell-based therapy in K/BxN serum transfer-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial hyperplasia and cartilage/bone destruction with systemic comorbidities. Despite advances in understanding the aetiology of RA and novel biologic drugs, a substantial number of individuals with RA remain intolerant or resistant to these therapies. In this context, mesenchymal stem/stromal cell (MSC)-based therapy has emerged as an innovative therapeutic alternative to address unresolved treatment issues for patients with RA thanks to the immunomodulatory properties of these cells. The majority of preclinical studies in MSC-based therapy have been conducted using the well-known collagen-induced arthritis (CIA) mouse model however due to its low incidence, the mouse strain restriction and the prolonged induction phase of collagen-induced arthritis, alternative experimental models of RA have been developed such as K/BxN serum transfer-induced arthritis (STIA), which mimics many of human RA features. In this study, we evaluate whether the K/BxN STIA model could be used as an alternative model to study the immunomodulatory potential of MSC-based therapy. Unexpectedly, our data suggest that adipose-derived MSC-based therapy is unsuitable for modulating the progression of K/BxN serum-transfer arthritis in mice despite the various experimental parameters tested. Based on the differences in the immune status and monocytic/macrophage balance among the different arthritic models, these results could help to identify the cellular targets of the MSCs and, most importantly to predict the RA patients that will respond positively to MSC-based therapy.

A Novel HDAC1-Selective Inhibitor Attenuates Autoimmune Arthritis by Inhibiting Inflammatory Cytokine Production.

Rheumatoid arthritis (RA) is systemic autoimmune arthritis that causes joint inflammation and destruction. Accumulating evidence has shown that inhibitors of class I histone deacetylases (HDACs) (i.e., HDAC1, 2, 3, and 8) are potential therapeutic candidates as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). Nevertheless, the inhibition of class I HDACs has severe adverse effects because of their broad spectrum. We evaluated the therapeutic effect of a novel selective HDAC1 inhibitor TTA03-107 for collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA) models in mice. We also examined the effect of TTA03-107 in bone marrow-derived macrophages (BMDMs) and T helper 17 (Th17) cells in vitro. Here, we delineate that TTA03-107 reduced the severity of autoimmune arthritis without obvious adverse effects in CIA and CAIA models. Moreover, TTA03-107 suppressed the production of inflammatory cytokines, such as interleukin (IL)-1β, tumor necrosis factor (TNF)-α, and IL-17A, in serum and joint tissue. In vitro treatment of BMDMs with TTA03-107 dampened the M1 differentiation and inflammatory cytokine production. TTA03-107 also suppressed the differentiation of Th17 cells. These results demonstrate that TTA03-107 can attenuate the development of arthritis in experimental RA models by inhibiting the differentiation and activation of macrophages and Th17 cells. Therefore, TTA03-107 is a potential tsDMARD candidate.

Physical Exercise and Low-Level Laser Therapy Systemic Effects on the Ankle Joint in an Experimental Rheumatoid Arthritis Model

ObjectiveThe purpose of this study was to analyze the systemic effects of stair climbing exercise, low-level laser therapy (LLLT), and the association of both treatments on pelvic member functionality and ankle joint histomorphometric aspects of Wistar rats submitted to experimental rheumatoid arthritis (RA) protocol. MethodsMale Wistar rats were randomly distributed into the following 8 groups: control; control LLLT; control exercise; control LLLT and exercise; arthritis group; arthritis LLLT; arthritis exercise; and arthritis LLLT and exercise, with n = 8 for functional and n = 5 for histomorphometrical tests. The experimental RA was induced by complete Freund adjuvant injection in the knee joint cavity. Functionality was evaluated by proprioception and motor function using Sciatic Functional Index and maximum angle reached at an inclined plane. Histomorphometrical aspects were evaluated in the ankle joint after histological routine. ResultsThe arthritis LLLT and exercise group had positive effects in Sciatic Functional Index (F [3.96] = 11.3, P < .001) and in inclined plane (F [3.4] = 36.1, P < .001). The arthritis exercise group presented a greater number of chondrocytes in the tibia (Wald [1; 6605.6] = 25.2, P < .001) and talus (Wald [1; 15958.6] = 19.8, P = .006) in relation to the other groups. The arthritis group morphology showed significant degenerative lesions as subintima with angiogenesis, inflammatory cells, flocculated articular cartilage, chondrocytes disorganization and pannus. Even with the higher chondrocytes number, the arthritis exercise group had morphological characteristics more similar to the control group. ConclusionLow-level laser therapy and exercise restored functionality, and exercise restored morphological aspects of tissues in experimentally induced RA in rats.

CdSe magic-sized quantum dots attenuate reactive oxygen species generated by neutrophils and macrophages with implications in experimental arthritis

The biological applicability of nanomaterials has been limited due to cytotoxicity. Studies have described the effects of nanomaterials on different tissues and cell types, but their actions on immune cells are less elucidated. This study describes unprecedented in vitro and in vivo antioxidant activities of cadmium selenide magic-sized quantum dots (CdSe MSQDs) with implications on rheumatoid arthritis. While the generation of ROS induced by nanomaterials is linked to cytotoxicity, we found that CdSe MSQDs reduced ROS production by neutrophils and macrophages following opsonized-zymosan stimuli, and we did not find cytotoxic effects. Interestingly, inherent antioxidant properties of CdSe MSQDs were confirmed through DPPH, FRAP, and ORAC assays. Furthermore, CdSe MSQDs reduced ROS levels generated by infiltrating leukocytes into joints in experimental model of rheumatoid arthritis. Briefly, we describe a novel application of CdSe MSQDs in modulating the inflammatory response in experimental rheumatoid arthritis through an unexpected antioxidant activity.

Impact of delayed type hypersensitivity arthritis on development of heart failure by aortic constriction in mice.

Patients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta. Aorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls. Significant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced. DTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.

Role of Suppressor of cytokine signaling 2 during the development and resolution of an experimental arthritis

Rheumatoid arthritis(RA) is a debilitating chronic inflammatory disease. Suppressors of Cytokine Signaling(SOCS) proteins regulate homeostasis and pathogenesis in several diseases. The intersection between RA pathophysiology and SOCS2 is unclear. Herein, we investigated the roles of SOCS2 during the development of an experimental antigen-induced arthritis(AIA). In wild type mice, joint SOCS2 expression was reduced during AIA development. At the peak of inflammation, SOCS2-/- mice presented with reduced numbers of infiltrated cells in their joints. At the late phase of AIA, however, exhibited increased adhesion/infiltration of neutrophils, macrophages, CD4+-T cells, CD4+CD8+-T cells, and CD4-CD8--T cells associated with elevated IL-17 and IFN-γ levels, joint damage, proteoglycan loss, and nociception. SOCS2 deficiency resulted in lower numbers of apoptotic neutrophils and reduced efferocytosis. The present study demonstrated the vital role of SOCS2 during the development and resolution of an experimental RA model. Hence, this protein may be a novel therapeutic target for this disorder.