Pathology Of Rheumatoid Arthritis Research Articles

Dietary omega-3 fatty acids modulate the production of platelet-derived microvesicles in an in vivo inflammatory arthritis model.

The aim of this study was to investigate the effects of different ω-3 polyunsaturated fatty acid (PUFA) enriched diets, including a novel renewable plant source of ω-3 fatty acids (Buglossoides arvensis), on the development and progression of rheumatoid arthritis (RA). RA was induced in mice consuming experimental diets using the K/BxN model. The experimental diets consisted of either a western control diet (control), diets containing B. arvensis oil or fish oil. The effects of the diets on platelets, platelet microvesicles (PMVs), and inflammatory markers such as clinical index, ankle thickness and cytokine/chemokine release were measured. While ω-3 PUFA-enriched diets did not prevent the development of arthritis in the K/BxN model, a significant decrease in ankle swelling was observed compared to the control group. Platelets isolated from mice consuming either low content of B. arvensis oil or fish oil diets exhibited significantly decreased PMVs production compared to mice consuming the control diet. Our study provides insight into the contribution of ω-3 PUFA supplementation in modulating the pro-inflammatory phenotype of platelets in RA pathology. Furthermore, our study suggests that low concentrations of dietary B. arvensis oil may have similar anti-inflammatory potential seen with dietary fish oil supplementation.

Epi-revolution in rheumatology: the potential of histone deacetylase inhibitors for targeted rheumatoid arthritis intervention.

Autoimmune diseases hold significant importance in the realm of medical research, prompting a thorough exploration of potential therapeutic interventions. One crucial aspect of this exploration involves understanding the intricate processes of histone acetylation and deacetylation. Histone acetylation, facilitated by histone acetyl transferases (HATs), is instrumental in rendering DNA transcriptionally active. Conversely, histone deacetylases (HDACs) are responsible for the removal of acetyl groups, influencing gene expression regulation. The upregulation of HDACs, observed in various cancers, has steered attention towards histone deacetylase inhibitors (HDACi) as promising anti-cancer agents. Beyond cancer, HDACi has demonstrated anti-inflammatory properties, prompting interest in their potential therapeutic applications for inflammatory diseases such as rheumatoid arthritis (RA). RA, characterized by the immune system erroneously attacking healthy cells, leads to joint inflammation. Recent studies suggest that HDACi could offer a viable therapeutic strategy for RA, with potential mechanisms including the inhibition of synovial tissue growth and suppression of pro-inflammatory cytokines. Furthermore, HDACi may exert protective effects on bone and cartilage, common targets in RA pathology. In-depth investigations through in vivo and histopathology studies contribute to the ongoing discourse on the therapeutic benefits of HDACis in the context of RA treatment.

White adipose tissue, a novel antirheumatic target: Clues from its secretory capability and adipectomy-based therapy.

White adipose tissue (WAT) is involved in rheumatoid arthritis (RA). This study explored its potential as an antirheumatic target. WAT status of healthy and adjuvant-induced arthritis (AIA) rats were compared. The contribution of WAT to RA pathology was evaluated by pre-adipocyte transplant experiments and by dissecting perirenal fat pads of AIA rats. The impact of RA on WAT was investigated by culturing pre-adipocytes. Proteins differentially expressed in WAT of healthy and AIA rats were identified by the UPLC/MS2 method. These together with PPARγ siRNA and agonist were used to treat pre-adipocytes in vitro. The medium was used for THP-1 monocyte culture. Compared with healthy controls, AIA WAT was smaller but secreted more leptin, eNAMPT, MCP-1, TNF-α, and IL-6. AIA rat pre-adipocytes increased the levels of these adipokines in healthy recipients. RA patients' serum induced a similar secretion change and impaired differentiation of pre-adipocytes. Adipectomy eased AIA-related immune abnormalities and arthritic manifestations. Hepatokines PON1, IGFBP4, and GPIHBP1 were among the differential proteins in high levels in RA blood, and induced inflammatory secretions by pre-adipocytes. GPIHBP1 inhibited PPARγ expression and caused differentiation impairment and inflammatory secretion by pre-adipocytes, a similar outcome to PPARγ-silencing. This endowed the cells with an ability to activate monocytes, which can be abrogated by rosiglitazone. Certain hepatokines potentiate inflammatory secretions by pre-adipocytes and expedite RA progression by inhibiting PPARγ. Targeting this signalling or abnormal WAT secretion by various approaches may reduce RA severity.

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.Graphic

The Role of Semaphorins in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Inflammation of the synovial fluid propagates the pathological process of angiogenesis. Semaphorins play a crucial role in the context of endothelial cell function, and their pleiotropic nature has various effects on the further development of RA. This narrative review summarises the various roles of semaphorins in the pathology of RA and whether they could play a role in developing novel RA treatment options.

ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

Circ_0011058 alleviates RA pathology through the circ_0011058/miR-335-5p/CUL4B signal axis

Our previous study found that Cullin 4B (CUL4B) inhibited rheumatoid arthritis (RA) pathology through glycogen synthase kinase-3beta (GSK3β)/canonical Wnt signalling pathway. In this work, pre-experiment and bioinformatics analysis suggested that circ_0011058 may lead to the up-regulation of CUL4B expression by inhibiting miR-335-5p. Therefore, we studied whether circ_0011058 can promote the expression of CUL4B through sponging the miR-335-5p and further promote the pathological development of RA. Bioinformatics prediction, real-time quantitative PCR (RT-qPCR), western blot (WB), double luciferase reporter gene and other relevant methods were used to study the inhibition of circ_0011058 on RA pathology and its molecular mechanism. Results showed that the expression of circ_0011058 was significantly increased in adjuvant arthritis (AA) rats and RA fibroblast-like synoviocytes (FLS). The knockout of circ_0011058 inhibited the proliferation of AA FLS and RA FLS, decreased the levels of interleukin-1 beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), and inhibited the expression of matrix metalloproteinase 3 (MMP3), fibronectin, which showed that circ_0011058 had a strong role in promoting RA pathology. Furthermore, miR-335-5p expression was reduced in AA rats and RA FLS. The highly expressed circ_0011058 directly sponged the miR-335-5p, which led to the increase of CUL4B expression and promoted the activation of the GSK3β/canonical signalling pathway. Finally, we confirmed that miR-335-5p mediated the roles of circ_0011058 in promoting RA pathological development, which showed that the circ_0011058/miR-335-5p/CUL4B signal axis was involved in RA pathology. This work was of great significance for clarifying the roles of circ_0011058 in RA pathology, and further work was needed to establish whether circ_0011058 was a potential therapeutic target or diagnostic marker for RA.

Fat mass and obesity-associated protein inhibit the pathology of rheumatoid arthritis through the NSUN2/SFRP1/Wnt/β-catenin signal axis.

The purpose of this study is to investigate whether fat mass and obesity-associated protein (FTO) and NOL1/NOP2/Sun domain family member 2 (NSUN2) mediated RNA methylation is associated with RA pathology. We studied the anti-rheumatoid arthritis (RA) mechanism mediated by FTO and NSUN2 in RA samples and collagen-induced arthritis (CIA) rats using real time qPCR (RT-qPCR), western blot, immunofluorescence, and other methods. The expression of NSUN2 was significantly increased in both RA patients and CIA rats compared with normal controls. Knockdown of NSUN2 blocked the Wnt/β-catenin signaling pathway and inhibited RA pathological factors such as MMP3, fibronectin, and interleukins. FTO overexpression inhibited RA by inhibiting the expression of NSUN2, up-regulating the level of SFRP1 protein, and blocking the Wnt/β-catenin signaling pathway. NSUN2 overexpression interfered with the inhibitory effects of FTO on the Wnt/β-catenin signaling pathway and RA pathology, which further verified that FTO inhibited RA through the NSUN2/SFRP1/Wnt/β-catenin signal axis. FTO and NSUN2 are important factors of RA, and this work provides new potential diagnostic biomarkers and therapeutic targets for RA. We also reveal a gene expression regulation pattern of the interaction between m6A and m5C. revealing the pathogenesis of RA from the perspective of RNA methylation.

Isorhamnetin Downregulates MMP2 and MMP9 to Inhibit Development of Rheumatoid Arthritis through SRC/ERK/CREB Pathway.

To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis (RA). Tumor necrosis factor (TNF)- α -induced fibroblast-like synoviocytes (FLS) was exposed to additional isorhamnetin (10, 20 and 40 µ mol/L). Overexpression vectors for matrix metalloproteinase-2 (MMP2) or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function. RA-FLS viability, migration, and invasion were evaluated. Moreover, a collagen-induced arthritis (CIA) rat model was established. Rats were randomly divided to sham, CIA, low-, medium-, and high-dosage groups using a random number table (n=5 in each group) and administed with normal saline or additional isorhamnetin [2, 10, and 20 mg/(kg·day)] for 4 weeks, respectively. Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats. The levels of MMP2, MMP9, TNF-α, interleukin-6 (IL-6), and IL-1 β, as well as the phosphorylation levels of SRC, extracellular regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding (CREB), were detected in RA-FLS and synovial tissue. Molecular docking was also used to analyze the binding of isorhamnetin to SRC. In in vitro studies, isorhamnetin inhibited RA-FLS viability, migration and invasion (P<0.05). Isorhamnetin downregulated the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β in RA-FLS (P<0.05). The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion, as well as the levels of TNF-α, IL-6, and IL-1 β (P<0.05). Furthermore, isorhamnetin bound to SRC and reduced the phosphorylation of SRC, ERK, and CREB (P<0.05). SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability, migration and invasion, as well as the negative regulation of MMP2 and MMP9 (P<0.05). In in vivo studies, isorhamnetin decreased arthritis index scores (P<0.05) and alleviated synovial inflammation. Isorhamnetin reduced the levels of MMP2, MMP9, TNF-α, IL-6, and IL-1 β, as well as the phosphorylation of SRC, ERK, and CREB in synovial tissue (P<0.05). Notably, the inhibitory effect of isorhamnetin was more pronounced at higher concentrations (P<0.05). Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways, suggesting that isorhamnetin may be a potential therapeutic agent for RA.

Interplay of Systemic Immune-Inflammation Index and Serum Klotho Levels: Unveiling a New Dimension in Rheumatoid Arthritis Pathology.

Aim: The association between the systemic immune-inflammation index (SII) and serum Klotho concentrations (pg/ml) in patients with rheumatoid arthritis (RA) has not been elucidated. The purpose of this study was to clarify the relationship between the SII and serum Klotho concentrations in RA patients. Methods: All data come from the National Health and Nutrition Examination Survey (NHANES) database in the United States, which included 982 RA patients (age range: 40 to 79 years). The measurement data of the SII and serum Klotho are all from the NHANES mobile examination centre. We constructed a multivariate linear regression model to evaluate the association between the SII and serum Klotho levels in RA patients and conducted a subgroup analysis to test the stability of the statistical results. Results: Multivariate linear regression results indicated a negative linear relationship between the SII and serum Klotho concentrations in RA patients (β = -6.33, 95% CI [confidence interval]: -10.15 to -2.53). Compared to the quartile 1 group, the quartile 4 group was associated with significantly lower (P<0.001) serum Klotho concentrations (β = -120.93, 95% CI: -174.84 to -67.02). Compared with the quartile 1 group, with the increase in the SII, the β value showed a decreasing trend (P trend < 0.001). The subgroup analysis showed that none of the covariates affected the stability of these results (all P for interaction ≥ 0.05). Conclusion: There is a significant negative linear association between the SII and serum Klotho concentrations in RA patients. The SII can serve as a predictive indicator of serum Klotho concentrations in RA patients, and Klotho may be a potential anti-inflammatory target for RA treatment.

Scanning Electron Microscopic Analysis of the Bone-Resorption Activity in Mature Osteoclasts.

Bone homeostasis depends on the balance between bone deposition and bone resorption, which are mediated by the activity of osteoblasts and osteoclasts, respectively. Blocking osteoclast activity can be a therapeutic strategy in rheumatoid arthritis (RA) to reduce subsequent bone erosion. Therefore, investigating the activity of osteoclasts is essential for understanding the pathology of RA. Bone-resorption pits, which are caused by activated osteoclasts, are significantly increased in RA. Scanning electron microscopic analysis of bone-resorption pits is an effective method for understanding the pathology of RA. This chapter describes the method for observing the surface microstructure of pit formation on bone slices.

Histological Analyses of Arthritic Joints in Collagen-Induced Arthritis Model Mice.

Histological analysis is a morphological technique and an effective method for understanding the pathology of rheumatoid arthritis (RA). RA is an inflammatory disease characterized by increased synovial tissue and osteoclasts, angiogenesis, infiltration of inflammatory cells, and pannus formation. These pathologies can be observed in a collagen-induced arthritis model mouse using formaldehyde-fixated paraffin-embedded (FFPE) samples. For the preparation of FFPE samples, the conditions of the fixation and decalcification process significantly affect tissue staining results. Since the lesion sites include bone tissue, a decalcification process is necessary when preparing an FFPE sample. Therefore, selecting an optimal condition for the fixating and decalcifying solution is important. In this chapter, we describe the procedures of preparing paraffin samples, including fixation, decalcification, embedding, and sectioning from the RA model mouse, as well as different staining methods (hematoxylin and eosin, tartrate-resistant acidphosphatase).

SIRT1 inhibitors within Qing-Luo-Yin alleviated white adipose tissues-mediated inflammation in antigen-induced arthritis mice.

White adipose tissues (WAT) release large amounts of inflammatory mediators, which are responsible for the pathology of rheumatoid arthritis (RA). The current study investigated the involvement of WAT in the treatments of antigen-induced arthritis (AIA) mice with the herbal formula Qing-Luo-Yin (QLY). Cytokines and biochemical/metabolic indicators were determined by ELISA and colorimetry methods, respectively. Monocytes were analyzed by flow cytometry. Tissues were subjected to PCR, western-blot and histological analyses. Pre-adipocytes were cultured in the different mouse serum from the in vivo experiment, and some of them were treated by certain compounds or/and lipopolysaccharide. Afterwards, the catalytic activity and thermostability of SIRT1 were tested. Gene/protein expression and cytokine production were investigated too. NAMPT and SIRT1 were silenced in some cells by siRNA. AIA mice suffered from inflammatory adipokines-mediated metabolism and immune disorders. Besides joint protective effects, QLY therapies favored adipocyte differentiation and suppressed inflammatory adipokines release. The up-regulation of fatty acid oxidation and inflammatory monocyte polarization was therefore inhibited in peripheral tissues. PPARγ expression was generally promoted by QLY. Whereas, SIRT1 activity was always impaired, indicated by the declined NAD+ levels and the increased ace-p65 expression. QLY effectively inhibited eNAMPT release in AIA mouse serum-cultured pre-adipocytes. This effect was antagonized by resveratrol (a SIRT1 agonist) and overshadowed by NAMPT silencing. QLY-related compounds berberine, dioscin and sophocarpine showed high binding affinities to SIRT1, stabilized this protein, and inhibited its deacetylation activity in vitro. Their effects on ace-p65 expression were weakened when SIRT1 was silenced. SIRT1 inhibitors in QLY reduced eNAMPT production and up-regulated PPARγ in AIA mice, leading to inflammation remission. These clues show that except for the well-known anti-inflammatory functions, SIRT1 participates in inflammatory reactions too and could be a potential anti-rheumatic target.

Effect of basal metabolic rate on rheumatoid arthritis: a Mendelian randomization study.

Basal metabolic rate (BMR) as one of the most basic and significant indicators of metabolism has been associated with human health. Previous studies showed that the development of rheumatoid arthritis (RA) is linked to BMR; however, the causal relationship between BMR and RA is unknown. Thus, we aimed to explore the causal relationship between BMR and RA as well as RA-related factors. Mendelian randomization (MR) analysis was performed on collected genome-wide association studies information. The effect of horizontal pleiotropy was detected by MR-PRESSO and MR-Radial. Five MR analysis methods were applied, including inverse variance weighted, MR-Egger, weighted median, weighted mode, and simple mode. Four sensitivity analysis methods were used for the validation of the significant MR analysis results. A two-component mixture of regressions method was additionally used to validate single nucleotide polymorphisms and to verify results. Genetically, there is a causal effect of BMR on overall RA (odds ratio = 1.25, 95% confidence interval: 1.07-1.47, PIVW = .006), seropositive RA (odds ratio = 1.20, 95% confidence interval: 1.01-1.44, PIVW = .035), and seronegative RA (odds ratio = 1.36, 95% confidence interval: 1.04-1.78, PIVW = .023). Sensitivity analyses validated the robustness of the above associations. No evidence supported the effect of RA on BMR. Moreover, BMR showed no causal relationship with rheumatoid factor, C-reactive protein, erythrocyte sedimentation rate, interleukin-1β, tumor necrosis factor-α, and matrix metallopeptidase 3. MR results implied the causal effect of BMR on RA and raised our attention to the importance of BMR in RA's pathology.

Deconstruction of rheumatoid arthritis synovium defines inflammatory subtypes

Rheumatoid arthritis is a prototypical autoimmune disease that causes joint inflammation and destruction1. There is currently no cure for rheumatoid arthritis, and the effectiveness of treatments varies across patients, suggesting an undefined pathogenic diversity1,2. Here, to deconstruct the cell states and pathways that characterize this pathogenic heterogeneity, we profiled the full spectrum of cells in inflamed synovium from patients with rheumatoid arthritis. We used multi-modal single-cell RNA-sequencing and surface protein data coupled with histology of synovial tissue from 79 donors to build single-cell atlas of rheumatoid arthritis synovial tissue that includes more than 314,000 cells. We stratified tissues into six groups, referred to as cell-type abundance phenotypes (CTAPs), each characterized by selectively enriched cell states. These CTAPs demonstrate the diversity of synovial inflammation in rheumatoid arthritis, ranging from samples enriched for T and B cells to those largely lacking lymphocytes. Disease-relevant cell states, cytokines, risk genes, histology and serology metrics are associated with particular CTAPs. CTAPs are dynamic and can predict treatment response, highlighting the clinical utility of classifying rheumatoid arthritis synovial phenotypes. This comprehensive atlas and molecular, tissue-based stratification of rheumatoid arthritis synovial tissue reveal new insights into rheumatoid arthritis pathology and heterogeneity that could inform novel targeted treatments.

Protein citrullination and NET formation do not contribute to the pathology of A20/TNFAIP3 mutant mice

A20 serves as a critical brake on NF-κB-dependent inflammation. In humans, polymorphisms in or near the TNFAIP3/A20 gene have been linked to various inflammatory disorders, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Experimental gene knockout studies in mice have confirmed A20 as a susceptibility gene for SLE and RA. Here, we examine the significance of protein citrullination and NET formation in the autoimmune pathology of A20 mutant mice because autoimmunity directed against citrullinated antigens released by neutrophil extracellular traps (NETs) is central to the pathogenesis of RA and SLE. Furthermore, genetic variants impairing the deubiquitinase (DUB) function of A20 have been shown to contribute to autoimmune susceptibility. Our findings demonstrate that genetic disruption of A20 DUB function in A20 C103R knockin mice does not result in autoimmune pathology. Moreover, we show that PAD4 deficiency, which abolishes protein citrullination and NET formation, does not prevent the development of autoimmunity in A20 deficient mice. Collectively, these findings provide experimental confirmation that PAD4-dependent protein citrullination and NET formation do not serve as pathogenic mechanisms in the development of RA and SLE pathology in mice with A20 mutations.

Conceptual Study of Shatpushpadi Lepa in Amavata

Amavata is most common disorder affecting the general population. Now a days, people have adopted unhealthy life style eating junk and doing vigorous exercise just after eating. In Ayurveda the causes of Amavata are Virudhha Ahara-Chesta, Mandagni, Nishchalata and doing Vyayama immediately after Snigdha Bhojana. The clinical presentation of Pravridhha Amavata closely resembles the Rheumatoid Arthritis. It is most common inflammatory arthritis and is major cause of disability. In Ayurveda various Deepana-Pachana, Aushadhis Sewana, Panchkarma therapies (Shushka Sweda, Virechana, Basti and Lepa) are mentioned in the treatment of Amavata. Shatpushpadi Lepa is one of the polyherbal compound mentioned by Acharaya Yogaratnakara in the management of Amavata. Almost all the ingredients of Shatpushpadi Lepa are having anti-inflammatory and analgesic properties. So, Lepa by its local application can combat the pathology in Rheumatoid Arthritis.

Dysregulation of B lymphocyte development in the SKG mouse model of rheumatoid arthritis.

Rheumatoid arthritis is a chronic and systemic inflammatory disease that affects approximately 1% of the world's population and is characterised by joint inflammation, the destruction of articular cartilage and bone, and many potentially life-threatening extraarticular manifestations. B lymphocytes play a central role in the pathology of rheumatoid arthritis as the precursors of autoantibody secreting plasma cells, as highly potent antigen-presenting cells, and as a source of various inflammatory cytokines, however, the effects of rheumatoid arthritis on B lymphocyte development remain poorly understood. Here, we analyse B lymphocyte development in murine models of rheumatoid arthritis, quantifying all the subsets of B cell precursors in the bone marrow and splenic B cells using flow cytometry. We demonstrate a severe reduction in pre-B cells and immature B cells in the bone marrow of mice with active disease, despite no major effects on the mature naïve B cell numbers. The loss of B cell precursors in the bone marrow of the affected mice was associated with a highly significant reduction in the proportion of Ki67+ cells, indicating impaired cell proliferation, while the viability of the B cell precursors was not significantly affected. We also observed some mobilisation of the B cell precursor cells into the mouse spleen, demonstrated with flow cytometry and pre-B colony forming units assays. In summary, the current work demonstrates a severe dysregulation in B lymphocyte development in murine rheumatoid arthritis, with possible implications for B cell repertoire formation, tolerance induction, and disease mechanisms.

The role of TRPV1 in RA pathogenesis: worthy of attention.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) is a Ca2+permeable, non-selective cation channel that is found primarily in sensory nerve fibres. Previous studies focused on pain transmission. However, recent studies have found that the TRPV1 channel, in addition to being associated with pain, also plays a role in immune regulation and their dysregulation frequently affects the development of rheumatoid arthritis (RA). A thorough understanding of the mechanism will facilitate the design of new TRPV1-targeted drugs and improve the clinical efficacy of RA. Here, we provide an updated and comprehensive overview of how the TRPV1 channel intrinsically regulates neuronal and immune cells, and how alterations in the TRPV1 channel in synoviocytes or chondrocytes extrinsically affect angiogenesis and bone destruction. Rapid progress has been made in research targeting TRPV1 for the treatment of inflammatory arthritis, but there is still much-uncharted territory regarding the therapeutic role of RA. We present a strategy for targeting the TRPV1 channel in RA therapy, summarising the difficulties and promising advances in current research, with the aim of better understanding the role of the TRPV1 channel in RA pathology, which could accelerate the development of TRPV1-targeted modulators for the design and development of more effective RA therapies.

Therapeutic Effect of Colony Stimulating Factor 1 Receptor Kinase Inhibitor, JTE-952, on Methotrexate-Refractory Pathology in a Rat Model of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by inflammation and the destruction of bone and cartilage in affected joints. One of the unmet medical needs in the treatment of RA is to effectively prevent the structural destruction of joints, especially bone, which progresses because of resistance to conventional drugs that mainly have anti-inflammatory effects, and directly leads to a decline in the QOL of patients. We previously developed a novel and orally available type II kinase inhibitor of colony-stimulating factor-1 receptor (CSF1R), JTE-952. CSF1R is specifically expressed by monocytic-lineage cells, including bone-resorbing osteoclasts, and is important for promoting the differentiation and proliferation of osteoclasts. In the present study, we investigated the therapeutic effect of JTE-952 on methotrexate (MTX)-refractory joint destruction in a clinically established adjuvant-induced arthritis rat model. JTE-952 did not suppress paw swelling under inflammatory conditions, but it inhibited the destruction of joint structural components including bone and cartilage in the inflamed joints. In addition, decreased range of joint motion and mechanical hyperalgesia after disease onset were suppressed by JTE-952. These results suggest that JTE-952 is expected to prevent the progression of the structural destruction of joints and its associated effects on joint motion and pain by inhibiting CSF1/CSF1R signaling in RA pathology, which is resistant to conventional disease-modifying anti-rheumatic drugs such as MTX.