Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease that currently has no cure. Fibroblast-like synoviocytes (FLS), present in the RA synovium, play a pivotal role in RA pathogenesis. Notably, FLS in the RA patients (RA-FLS) exhibit characteristics similar to cancer cells, like enhanced migration, invasiveness, uncontrolled proliferation, resistance to apoptosis, and metabolic reprogramming. RA-FLS invasiveness is linked to radiographic joint damage in the patients, whereas inhibiting the FLS migration mitigates disease pathology. However, the molecular mechanisms underlying the migration and invasion capabilities of RA-FLS are not entirely understood. In this work, we have explored the function of mitochondrial calcium uniporter (MCU) and calcium signaling in FLS invasion. Our findings demonstrate a positive correlation between MCU expression and RA disease score. Interestingly, mitochondrial size was reduced, and peripheral localization was more pronounced in the RA-FLS when compared to the control FLS. Mitochondrial calcium import inhibition in the FLS by specific MCU inhibitor, Ruthenium-360 restored these altered mitochondrial dynamics and reduced the invasive phenotype. Through unbiased transcriptome analysis, we identified that MCU-mediated calcium signaling in RA-FLS leads to the enriched actin cytoskeleton and focal adhesion pathways responsible for the invasion phenotype, which can be effectively suppressed by inhibiting MCU. Additionally, we found that mitochondrial transport facilitator Miro1 binds to MCU in a calcium-dependent manner and regulates MCU-mediated mitochondrial dynamics and RA-FLS invasion. Experiments utilizing mice xenograft model demonstrated that MCU silencing diminishes the migration of RA-FLS toward the sites of inflammation in the immunocompromised SCID mice. Altogether, our findings highlight MCU as a promising therapeutic target to inhibit RA-FLS migration and RA progression.

Rheumatoid arthritis (RA) is a common chronic autoimmune disease characterised by the proliferation and infiltration of fibroblast-like synoviocytes (FLS). However, pharmaceutical approaches to inhibit FLS in the treatment of RA are limited. Berbamine (BBM), a natural compound extracted from Phellodendron chinense Schneider, has demonstrated anti-tumour and anti-inflammatory effects. This study aimed to investigate the inhibitory effect of BBM on FLS in RA and to delineate the specific mechanisms involved, thereby proposing a novel therapeutic strategy for RA. Using the cell counting kit 8 assay and flow cytometry, we found that BBM reduced the proliferative ability of MH7A rheumatoid arthritis fibroblast-like synoviocytes by blocking the cell cycle and inducing apoptosis. In addition, BBM led to a decrease in the mitochondrial membrane potential and an increase in reactive oxygen species (ROS) and DNA damage. To explore the explicit mechanism of BBM, we used the ROS inhibitor N-acetyl-L-cysteine and the anti-apoptotic drug Z-VAD-FMK to rescue the effects of BBM. BBM effectively inhibited joint inflammation in RA cells in vivo. Regarding the safety confirmation, BBM does not damage the liver, spleen, and kidneys of collagen-induced arthritis mice. In summary, we found that the traditional Chinese medicine extract BBM alleviated RA by promoting ROS production and DNA damage in rheumatoid arthritis fibroblast-like synoviocytes providing new ideas for the clinical treatment of RA with traditional Chinese medicine.

For the treatment of rheumatoid arthritis (RA), there are limited options for drugs with fewer side effects. Neferine possesses anti-inflammatory, anti-fibrotic, and cardioprotective properties, but its effectiveness in the treatment of RA remains unclear. Our study aimed to explore the impact of neferine administration on ankle joint inflammation and cardiac complications of collagen-induced arthritis (CIA) mice. The CIA model was introduced in male DBA/1 mice via subcutaneous injection of Type II collagen (CII) into the tail. We found that neferine alleviated ankle joint inflammation, cartilage erosion, and bone destruction, as well as reduced the levels of IL-6, TNF-α, IL-1β, and IL-18 in the serum of CIA mice. Furthermore, neferine reduced the expression of synovial damage markers (RANKL, MMP-3, and MMP-13) in the ankle joints of CIA mice. Mechanistically, neferine lowered the levels of NF-κB pathway-related molecules such as p-IκBα, p-p65, and nuclear p65 in the synovial tissue of CIA mice. Simultaneously, neferine reversed the upregulation of NLRP3, ASC, and cleaved-caspase-1 levels in the synovial tissue of CIA mice. Additionally, our results showed that neferine reduced the contents of myocardial injury markers (cTnI, CK-MB, and LDH), alleviated myocardial fibrosis, decreased expression of α-SMA and Collagen I, as well as mitigated the activation of fibrosis-related TGF-β/Smad signaling. In summary, our study demonstrates that neferine attenuates chondral and synovial inflammation in a CIA mouse model by inhibiting the activation of the NF-κB/NLRP3 inflammasome, and neferine has a protective effect on the hearts of CIA mice.

The synovium maintains joint homeostasis and regulates immune responses through fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS). However, investigation of the intricate FLS-MLS interactions is limited by the lack of physiologically relevant in vitro models. Here, this work presents a synovium-on-a-chip model that faithfully mimics the structural and functional properties of the human synovial lining, established with collagen/alginate hybrid hydrogel (CAHG). The functional phenotype of FLS observed in vivo is replicated on chip when cultured with CAHG. Moreover, co-culture with M2c macrophages derived from CD14+ monocytes enables the reconstruction of key immune functions of the synovial lining, including expression of junction proteins (ZO-1 and CLD5) and immunoregulatory markers (TREM2 and VSIG4). CD44 blockade, disrupting FLS-MLS interactions, significantly suppresses inflammasome-related pathways, underscoring the regulatory role of FLS in synovial immune responses. Our model is further validated by modeling gout, where treatment with monosodium urate crystals trigger NLRP3 inflammasome activation, macrophage polarization, and neutrophil extravasation. Pharmacological interventions with MCC950 and entrectinib effectively inhibit the inflammasome activation, demonstrating the platform's utility for preclinical drug evaluation. This synovium-on-a-chip provides a reliable in vitro model for studying synovial inflammation and serves as a valuable tool for the therapeutic discovery of inflammatory joint diseases.

Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.

This study aimed to explore the protective effects of berberine against rheumatoid arthritis (RA) and clarify the role of activating transcription factor 3 (ATF3) in the mechanism of action of berberine, using a lipopolysaccharide (LPS)-stimulated SW982 human synovial cell line. Berberine treatment resulted in a concentration-dependent reduction in LPS-induced proinflammatory cytokines and matrix metalloproteinases (MMPs) in SW982 cells. These inhibitory effects were associated with increased ATF3 expression, reduced nuclear translocation of nuclear factor-κB (NF-κB), and diminished phosphorylation of mitogen-activated protein kinase (MAPK). In contrast, ATF3 knockdown reversed the suppressive effects of berberine on proinflammatory cytokines and MMP production, leading to enhanced MAPK phosphorylation; however, it had minimal impact on adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Furthermore, AMPK knockdown negated the protective effects of berberine and reduced ATF3 levels, whereas treatment with 5-aminoimidazole-4-carboxamide ribonucleotide, an AMPK activator, replicated the beneficial effects of berberine. In an in vivo collagen-induced arthritis (CIA) mouse model, intraperitoneal administration of berberine significantly reduced paw edema and arthritis severity, accompanied by ATF3 induction and increased AMPK phosphorylation in the synovial tissue. These findings highlighted the pivotal role of ATF3 in mediating the protective effects of berberine in RA- and LPS-activated synoviocytes, suggesting its potential as a therapeutic agent for RA management.

Pathologic tissue remodeling with scarring and tissue rigidity has been demonstrated in inflammatory, autoimmune, and allergic diseases. Eosinophilic esophagitis (EoE) is an allergic disease that is diagnosed and managed by repeated biopsy procurement, allowing an understanding of tissue fibroblast dysfunction. While EoE-associated tissue remodeling causes clinical dysphagia, food impactions, esophageal rigidity, and strictures, molecular mechanisms driving these complications remain under investigation.

We hypothesized that chronic EoE inflammation induces pathogenic fibroblasts with dysfunctional tissue regeneration and motility.

We used single-cell RNA sequencing, fluorescence-activated cell sorting analysis, and fibroblast differentiation and migration assays to decipher the induced and retained pathogenic dysfunctions in EoE versus healthy esophageal fibroblasts.

Differentiation assays demonstrated that active EoE fibroblasts retain regenerative programs for rigid cells such as chondrocytes (P < .05) but lose healthy fibroblast capacity for soft cells such as adipocytes (P < .01), which was reflected in biopsy sample immunostaining (P < .01). EoE, but not healthy, fibroblasts show proinflammatory and prorigidity transcriptional programs on single-cell RNA sequencing. In vivo, regenerative fibroblasts reside in perivascular regions and near the epithelial junction, and during EoE, they have significantly increased migration (P < .01). Flow analysis and functional assays demonstrated that regenerative EoE fibroblasts have decreased surface CD73 expression and activity (both P < .05) compared to healthy controls, indicating aberrant adenosine triphosphate handling. EoE fibroblast dysfunctions were induced in healthy fibroblasts by reducing CD73 activity and rescued in EoE using adenosine repletion.

A normalization of perturbed extracellular adenosine triphosphate handling and CD73 could improve pathogenic fibroblast dysfunction and tissue regeneration in type 2 inflammatory diseases.

Huntingtin-interacting protein 1-related (HIP1R) shares some function similarities with HIP1, and HIP1 regulates arthritis and RA fibroblast-like synoviocytes (FLS) invasiveness. Therefore, we hypothesized that HIP1R might be involved in the regulation of FLS phenotypes and molecular processes relevant to RA. siRNA was used to knockdown HIP1R, HIP1 or control in RA FLS, followed by cell studies for invasion in Matrigel, migration, proliferation, and adhesion. RNA was sequenced and analyzed. HIP1R knockdown significantly reduced RA FLS invasiveness and migration (p < 0.05). The DEGs in siRNA HIP1R had an enrichment for GO processes "astrocyte and glial cell projection", "small GTPase signaling", and "PDGFR signaling". The most significantly DEGs had decreased expression in siRNA HIP1R and included AKT1S1, GABBR2, GPR56, and TXNDC12. siRNA HIP1 RA FLS had an enrichment for the "Rap1 signaling pathway" and "Growth factor receptor binding". The most significantly DEGs in HIP1 siRNA included FGF2, PGF, and SLC39A8. HIP1R and HIP1 DEG lists had a greater than expected number of similar genes (p = 0.0015), suggesting that, despite the major differences detected, both have partially overlapping functions in RA FLS. The most significantly DEGs in both HIP1R and HIP1 analyses are involved in cancer cell behaviors and outcomes. HIP1R is a new gene implicated in RA FLS invasiveness and migration, and regulates unique pathways and cell processes relevant to both RA as well as cancer biology. Our study provides new insight into processes implicated in FLS invasiveness, which is relevant for joint damage in RA, and identify new potential gene targets for FLS-specific treatments.

Rheumatoid arthritis (RA) is a chronic autoimmune disease distinguished by inflammatory synovitis. Chrysin can alleviate the inflammatory response and inhibit the progression of RA. However, unfavorable physicochemical properties and nonselective biodistribution of chrysin make it difficult to achieve good therapeutic efficacy. To address these challenges, we developed a biomimetic nanocarrier to enhance the targeted delivery of chrysin to synoviocytes, a key cellular component in RA pathology. Our nanodrug, FMPlipo@C, was engineered by integrating fibroblast-like synoviocyte (FLS) membrane proteins into chrysin-loaded liposomes. This innovative approach harnesses homologous targeting mediated by FLS membrane proteins to direct liposomes to inflamed joints, facilitating cargo release within synoviocytes. We showed that FMPlipo@C reduces inflammation in collagen-induced rheumatoid arthritis (CIA) model mice by inhibiting the HIF-1α/iNOS/NLRP3 pathway, protecting cartilage, and preventing bone erosion, thus reducing swelling and stiffness. This study offers valuable insights into the development of novel therapeutic strategies for the treatment of RA.

Rheumatoid arthritis (RA), a prevalent autoimmune disease, features inflammation and bone erosion, correlating with osteoclast hyperactivation and enhanced responsiveness to inflammatory factors. Reducing osteoclast formation and inflammatory mediator expression might avert bone erosion in RA. Carboxyaminotriazole (CAI) holds potential for treating autoinflammatory disorders and impeding cancer-related bone metastases. Yet, its bone-protective role and mechanism remain elusive. This study targets to explore the impacts and underlying mechanisms of CAI in preventing bone erosion in RA.

A collagen-induced arthritis (CIA) rat model was utilized to evaluate the anti-RA potential of CAI. CCK-8, TRAP staining, TRAP activity assay, pit formation assay, RT-qPCR, Western blotting, immunofluorescence, and ELISA, were conducted to assess the effects and potential mechanisms of CAI in the management of RA.

CAI not only reduces inflammatory symptoms, but it also offers superior bone protection compared to methotrexate (MTX) and works synergistically with MTX, the preferred anchoring agent for the treatment of RA. In vitro studies show that CAI inhibits osteoclast differentiation and function, as well as the expression of specific genes, by inhibiting NF-κB/MAPK pathways and reducing IL-1β levels. The deletion of Il-1 and the application of IL-1β inhibitors suggest that CAI retards osteoclastogenesis through the downregulation of IL-1β.

CAI may have therapeutic value in treating RA-related bone erosion, likely due to its inhibition of overactive osteoclasts by suppressing the NF-κB/MAPK pathways and the subsequent expression of IL-1β.

Fibroblast-like synoviocytes (FLS) are key cells promoting cartilage damage and bone loss in rheumatoid arthritis (RA). They are activated to assume an invasive and migratory phenotype. While mechanisms of FLS activation are unknown, evidence suggests that pre-damaged extracellular matrix (ECM) of the cartilage can trigger FLS activation. Integrin α11β1 might be involved in the activation, as it is increased in RA patients and hTNFtg mice, an RA mouse model. We treated murine chondrocytes with TNFα to produce a damaged, RA-like matrix. Comparison to healthy chondrocyte matrix revealed decreased ECM proteins, e.g. collagens and proteoglycans, increased matrix-degrading proteins and elevated levels of inflammatory cytokines. FLS responded to the damaged chondrocyte matrix with a matrix-remodeling and pro-inflammatory phenotype characterized by a gene signature involved in matrix degradation and increased production of CLL11 and CCL19. Damaged chondrocyte matrix stimulated increased Itga11 expression in FLS, correlating with the increased α11β1 amounts in RA patients. FLS deficient in integrin α11β1 released lower amounts of inflammation-associated cytokines. Our results demonstrate differences in healthy and RA-like chondrocyte ECM and distinctly different responses of wt FLS to damaged versus healthy ECM.

Gout is a crystal-related arthropathy caused by monosodium urate (MSU) deposition, resulting from purine metabolism disorders and hyperuricemia (HUA). Gout belongs to the traditional medicine category of Bi syndrome. Biqi capsules (BQ) is a traditional Chinese medicine formula used to treat Bi syndrome. The BQ prescription is derived from the ancient prescription of Hua Tuo, a famous physician in the Han Dynasty.

To study the effect and mechanism of BQ in treating acute gouty arthritis (AGA) and HUA.

Analyzing BQ's signaling pathways for gout treatment via network pharmacology. The HUA model was induced orally with adenine and potassium oxonate. The rat AGA model was established by MSU injection. In vitro, MH7A and RAW 246.7 cells were treated with LPS and MSU. Serum uric acid, creatinine, and urea nitrogen levels were evaluated. Kidney and ankle joint pathology was observed via HE staining. Inflammatory signaling pathway proteins, epithelial-mesenchymal transition (EMT) pathway proteins, and uric acid metabolism-related proteins were detected by Western blot.

1780 potential targets for gout treatment were identified, and 1039 target proteins corresponding to BQ's active ingredients were obtained. Pathway enrichment analysis revealed BQ improved gout mainly through inflammatory pathways. Experimental results showed BQ could reduce serum uric acid level and increase uric acid clearance rate by regulating the expression of adenosine deaminase (ADA), and organic anion transporter 1 (OAT1) and glucose transporter 9 (GLUT9) in HUA mice. BQ could improve renal function and injury by inhibiting the NLRP3 pathway in HUA mice' kidneys. Additionally, BQ could alleviate ankle joint swelling and synovial injury, inhibit the TLR4/NLRP3 pathway, and reduce levels of inflammatory factors including interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) in AGA rats. The main component of BQ, brucine, could inhibit the activation of NLRP3/NF-κB pathway induced by MSU and reduce the expression level of inflammatory factors (IL-6, IL-1β, and TNF-α) in macrophages. Brucine could inhibit the activation of the EMT pathway and reduce the expression level of inflammatory factors (IL-6, TNF-α) in human fibroblast-like synoviocytes (MH7A cells) induced by MSU.

BQ effectively reduced serum uric acid levels, improved kidney and joint damage, and ameliorated the inflammatory response caused by MSU. Its main component, brucine, effectively improved the inflammatory response and reduced the invasive ability of synoviocytes induced by MSU.

High-throughput technologies in human and animal studies have revealed novel molecular and cellular pathways involved in tissue inflammation of rheumatoid arthritis (RA). Fibroblasts have been in the forefront of research for several decades. Subpopulations with specific phenotypic and functional properties have been characterized both in mouse models and human disease. Data supporting the active involvement of fibroblasts in immune responses and tissue remodeling processes, as well as their central role in promoting clinical relapses and contributing to treatment resistance, have clearly reshaped their role in disease evolution. The lung is an important non-synovial component of RA both from a clinical and an immunopathogenic aspect. Interstitial lung disease (ILD) is a significant contributor to disease burden affecting morbidity and mortality. Although our knowledge of ILD has progressed, significant gaps in both basic and clinical science remain, posing hurdles to efficient diagnosis, prediction of disease course and its effective treatment. The specific role and contribution of fibroblasts to this process has not been clearly defined. The focus of this review is on fibroblasts and their contribution to RA and RA-ILD, presenting data on genetics and immune responses associated with RA-ILD in humans and animal models.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by inflammation in the synovial tissue, driven by aberrant activation of both the innate and adaptive immune systems, which can lead to irreversible disability. Despite the increasing therapeutic approaches for RA, only a low percentage of patients achieve sustained disease remission, and the persistence of immune dysregulation is likely responsible for disease recurrence once remission is attained. Cell therapy is an attractive, wide-spectrum strategy to modulate inflammation, and mesenchymal stromal cells (MSC) derived from perinatal tissues provide valuable tools for their use in regenerative medicine, mainly due to their immunomodulatory properties. Several in vitro studies have shown that perinatal MSC modulate the proliferation, maturation, and cytokine secretion profile of both innate and adaptive immune cells. Moreover, different beneficial effects have also been described when perinatal MSC were used to treat animal models of diseases associated with inflammatory conditions and degenerative processes. Specifically, in experimental models of RA, treatment with perinatal MSC resulted in a strong reduction of articular damage, which was associated with the modulation of both inflammation and activation of stromal resident cells in the synovial tissue. Here, we present in vitro and in vivo evidence supporting the use of perinatal MSC in RA. We also highlight the promising results from the few published clinical trials, which demonstrate the safety of perinatal MSC.

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease characterized with symmetrical progression of joint deformity that is often diagnosed at a chronic condition with other associated pathological conditions such as pericarditis, keratitis, pulmonary granuloma. Despite the understanding of RA pathophysiology in disease progression, current clinical treatment options such as disease-modifying anti-rheumatic drugs (DMARDs), biologics, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) provide only palliative therapy while causing adverse side effects such as off-target multi-organ toxicity and risk of infections. Further, available drug delivery strategies to treat RA pathogenicity does not successfully reach the site of action due to various barriers such as phagocytosis and first pass effect in addition to the disease complexity and unknown etiology, thereby leading to the development of irreversible joint dysfunction. Therefore, novel and effective strategies remain an unmet need to control the disease progression and to maintain the balance between pro- and anti-inflammatory cytokines. This review provides a comprehensive outlook on the RA pathophysiology and its corresponding disease progression. Contributions of synoviocytes such as macrophages, fibroblast-like cells in increasing invasiveness to exacerbate joint damage is also outlined in this review, which could be a potential future therapeutic target to complement the existing treatment regimens in controlling RA pathogenesis. Further, various smart drug delivery approaches under research to achieve maximum therapeutic efficacy with minimal adverse side effects have been discussed, which in turn emphasize the unmet challenges and future perspectives in addressing RA complications.

Rheumatoid arthritis (RA) is an enduring autoimmune inflammatory condition distinguished by continual joint inflammation, hyperplasia of the synovium, erosion of bone, and deterioration of cartilage.Fibroblast-like synoviocytes (FLSs) exhibiting "tumor-like" traits are central to this mechanism.ADP-ribosylation factor-like 4c (ARL4C) functions as a Ras-like small GTP-binding protein, significantly impacting tumor migration, invasion, and proliferation.However, it remains uncertain if ARL4C participates in the stimulation of RA FLSs exhibiting "tumor-like" features, thereby fostering the advancement of RA. In our investigation, we unveiled, for the inaugural instance, via the amalgamated scrutiny of single-cell RNA sequencing (scRNA-seq) and Bulk RNA sequencing (Bulk-seq) datasets, that activated fibroblast-like synoviocytes (FLSs) showcase high expression of ARL4C, and the ARL4C protein expression in FLSs derived from RA patients significantly surpasses that observed in individuals with osteoarthritis (OA) and traumatic injury (trauma).Silencing of the ARL4C gene markedly impeded the proliferation of RA FLSs by hindered the transition of cells from the G0/G1 phase to the S phase, and intensified cell apoptosis and diminished the migratory and invasive capabilities. Co-culture of ARL4C gene-silenced RA FLSs with monocytes/macrophages significantly inhibited the polarization of monocytes/macrophages toward M1 and the repolarization of M2 to M1.Furthermore, intra-articular injection of shARL4C significantly alleviated synovial inflammation and cartilage erosion in collagen-induced arthritis (CIA) rats. In conclusion, our discoveries propose that ARL4C assumes a central role in the synovial inflammation, cartilage degradation, and bone erosion associated with RA by triggering the PI3K/AKT and MAPK signaling pathways within RA FLSs.ARL4C holds promise as a prospective target for the development of pharmaceutical agents targeting FLSs, with the aim of addressing RA.

Considerable evidence indicates that CYP2E1 is associated with a variety of inflammatory diseases. Here we evaluated CYP2E1 as a potential therapeutic target for rheumatoid arthritis (RA) and established the protective effect of a new CYP2E1 inhibitor. Gene-expression datasets were used to analyze the change in expression of CYP2E1 in RA patients; CYP2E1 activity in collagen-induced arthritis (CIA) rats was determined by HPLC. We further evaluated the protective effects of Cyp2e1 knockout and a CYP2E1-specific inhibitor, Q11, synthesized by our group, in CIA and adjuvant-induced arthritis (AIA) rats. The expression of CYP2E1 in synovial tissue was elevated in RA patients and in CIA rats and the activity of CYP2E1 in vivo and in vitro in CIA rats was greater than that of controls. Cyp2e1 knockout significantly reduced the incidence of CIA and alleviated the severity of symptoms. Treatment with different doses of Q11 decreased paw thickness, volume and arthritis scores and reduced the serum levels of IL-6, TNF-α, IL-1β and MDA, and increased the level of GSH in CIA rats. A similar inhibitory effect was exhibited for Q11 in the AIA rats. Moreover, Q11 significantly impeded proliferation, migration, and invasion of human rheumatoid arthritis synovial fibroblasts cells. Q11 decreased the release of ROS and enhanced Nrf2 nuclear translocation and HO-1 expression in the cell nucleus. Overall, our results indicated that CYP2E1 may be a new target for RA and Q11 has potential protective effects against RA by reducing oxidative stress and opposing the inflammatory response via the ROS/Nrf2/HO-1 signaling pathway.

Rheumatoid arthritis (RA) is a common autoimmune disorder characterized by exacerbated joint inflammation. Despite the well-documented accumulation of the serine protease granzyme B (GzmB) in RA patient biospecimens, little is understood pertaining to its role in pathobiology. In the present study, tenascin-C (TNC) - a large, pro-inflammatory extracellular matrix glycoprotein - was identified as a substrate for GzmB in RA. GzmB cleaves TNC to generate 3 fragments in vitro: a 130 kDa fragment that remains anchored to the matrix and 2 solubilized fragments of 70 and 30 kDa. Mass spectrometry results suggested that the 30 kDa fragment contained the pro-inflammatory TNC C-terminal fibrinogen-like domain. In the synovial fluids of patients with RA, soluble levels of GzmB and TNC were significantly elevated compared with healthy controls. Further, immunoblotting revealed soluble 70 and 30 kDa TNC fragments in the synovial fluids of patients with RA, matching TNC fragment sizes generated by GzmB cleavage in vitro. Granzyme K (GzmK), another serine protease of the granzyme family, also cleaves TNC in vitro; however, the molecular weights of GzmK-generated TNC fragments did not correspond to TNC fragment sizes detected in patients. Our data support that GzmB, but not GzmK, contributes to RA through the cleavage of TNC.

Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.

miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that Mir221/222 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated Mir221/222 gene expression in murine SFs. SF-specific overexpression of Mir221/222 in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. Mir221/222 overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of Mir221/222 revealed cell cycle inhibitors Cdkn1b and Cdkn1c, as well as the epigenetic regulator Smarca1. Single-cell ATAC-seq data analysis revealed increased Mir221/222 gene activity in pathogenic SF subclusters and transcriptional regulation by Rela, Relb, Junb, Bach1, and Nfe2l2. Our results establish an SF-specific pathogenic role of Mir221/222 in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.

Apurinic/apyrimidinic endonuclease 1 (APEX1) is a protein with elevated expression in synovial fluids from rheumatoid arthritis (RA) patients. However, its role in RA pathogenesis remains unexplored. This study investigated the influence of APEX1 on inflammatory pathways in fibroblast-like synoviocytes (FLS) isolated from RA patients.

FLS from RA patients (n = 5) were stimulated with recombinant tumor necrosis factor α (TNF-α) and interleukin (IL)-17. Subsequently, cells were treated with recombinant APEX1, and assessments were made on reactive oxygen species (ROS) production and mitochondrial membrane potential. Additionally, mRNA levels of IL-1 family members were quantified. Cell migration was evaluated through Transwell chamber assays, and levels of key secreted inflammatory cytokines were measured via enzyme-linked immunosorbent assay (ELISA).

The results demonstrated that APEX1 significantly reduced mitochondrial-specific ROS expression and restored mitochondrial membrane potential in TNF-α/IL-17-stimulated RA FLS. Furthermore, APEX1 treatments attenuated TNF-α/IL-17-induced activation of p38 MAPK, NF-κB, and PI3K 110 δ signaling pathways. Similarly, APEX1 significantly diminished TNF-α/IL-17-induced expression of inflammatory cytokines, including IL-1 family members, IL-6, IL-8, and vascular endothelial growth factor (VEGF). Notably, APEX1 downregulated cell migration of TNF-α/IL-17-treated RA FLS via inhibition of matrix metalloproteinase 3 (MMP3).

These findings collectively underscore the role of APEX1 as a key mediator of cytokine-amplified migration, modulating ROS and MMP3 in RA FLS, thus supporting its potential as a therapeutic target in RA treatment.

Integrins are key regulators of cell-matrix interactions during joint development and joint tissue homeostasis, as well as in the development of osteoarthritis (OA). The signalling cascades initiated by the interactions of integrins with a complex network of extracellular matrix (ECM) components and intracellular adaptor proteins orchestrate cellular responses necessary for maintaining joint tissue integrity. Dysregulated integrin signalling, triggered by matrix degradation products such as matrikines, disrupts this delicate balance, tipping the scales towards an environment conducive to OA pathogenesis. The interplay between integrin signalling and growth factor pathways further underscores the multifaceted nature of OA. Moreover, emerging insights into the role of endocytic trafficking in regulating integrin signalling add a new layer of complexity to the understanding of OA development. To harness the therapeutic potential of targeting integrins for mitigation of OA, comprehensive understanding of their molecular mechanisms across joint tissues is imperative. Ultimately, deciphering the complexities of integrin signalling will advance the ability to treat OA and alleviate its global burden.

Ferroptosis is a form of iron-dependent regulated cell death caused by the accumulation of lipid peroxides. In this review, we summarize research on the impact of ferroptosis on disease models and isolated cells in various types of arthritis. While most studies have focused on rheumatoid arthritis (RA) and osteoarthritis (OA), there is limited research on spondylarthritis and crystal arthropathies. The effects of inducing or inhibiting ferroptosis on the disease strongly depend on the studied cell type. In the search for new therapeutic targets, inhibiting ferroptosis in chondrocytes might have promising effects for any type of arthritis. On the other hand, ferroptosis induction may also lead to a desired decrease of synovial fibroblasts in RA. Thus, ferroptosis research must consider the cell-type-specific effects on arthritis. Further investigation is needed to clarify these complexities.

In the pathogenesis of osteoarthritis, various signaling pathways may influence the bone joint through a common terminal pathway, thereby contributing to the pathological remodeling of the joint. Semaphorins (SEMAs) are cell-surface proteins actively involved in and primarily responsible for regulating chondrocyte function in the pathophysiological process of osteoarthritis (OA). The significance of the SEMA family in OA is increasingly acknowledged as pivotal. This review aims to summarize the mechanisms through which different members of the SEMA family impact various structures within joints. The findings indicate that SEMA3A and SEMA4D are particularly relevant to OA, as they participate in cartilage injury, subchondral bone remodeling, or synovitis. Additionally, other elements such as SEMA4A and SEMA5A may also contribute to the onset and progression of OA by affecting different components of the bone and joint. The mentioned mechanisms demonstrate the indispensable role of SEMA family members in OA, although the detailed mechanisms still require further exploration.

Rheumatoid arthritis (RA) is a chronic immune-mediated joint inflammatory disorder associated with aberrant activation of fibroblast-like synoviocytes (FLS). Recently, FLS gained importance due to its crucial role in RA pathogenesis, and thus, targeting FLS is suggested as an attractive treatment strategy for RA. FLS-targeted approaches may be combined with disease-modifying antirheumatic drugs (DMARDs) and natural phytochemicals to improve efficacy in RA control and negate immunosuppression. In this study, we assessed the therapeutic effectiveness of DD NP HG in primary RA-FLS cells isolated from the synovial tissue of FCA-induced RA rats. We observed that DD NP HG had good biosafety for healthy FLS cells and, at higher concentrations, a mild inhibitory effect on RA-FLS. The combination therapy (DD NP HG) of MTX NP and PEITC NE in RA-FLS showed a higher rate of apoptosis with significantly reduced LPS-induced expression of pro-inflammatory cytokines (TNF-α, IL-17A, and IL-6) in arthritic FLS. Further, the gene expression studies showed that DD NP HG significantly down-regulated the mRNA expression of IL-1β, RANKL, NFATc1, DKK1, Bcl-xl, Mcl-1, Atg12, and ULK1, and up-regulated the mRNA expression of OPG, PUMA, NOXA and SQSTM1 in LPS-stimulated RA-FLS cells. Collectively, our results demonstrated that DD NP HG significantly inhibited the RA-FLS proliferation via inducing apoptosis, down-regulating pro-inflammatory cytokines, and further enhancing the expression of genes associated with bone destruction in RA pathogenesis. A nanotechnology approach is a promising strategy for the co-delivery of dual drugs to regulate the RA-FLS function and achieve synergistic treatment of RA.

Synovial abnormalities are modifiable targets for hand pain and osteoarthritis. We examined the prevalence and distribution of ultrasound-detected hand synovial abnormalities in a community-derived sample of older people in China.

Within the Xiangya Osteoarthritis Study, a community-based study, we assessed synovial hypertrophy (SH), joint effusion, and Power Doppler signal (PDS) on all fingers and thumbs of both hands using standardized ultrasound examinations (score: 0-3). We assessed distribution patterns of SH and effusion using χ2-test and interrelationships of SH and effusion in different joints and hands by generalized estimating equations.

Among 3,623 participants (mean age: 64.4 years; women: 58.1%), prevalence of SH, effusion and PDS were 85.5%, 87.3% and 1.5%, respectively. Prevalence of SH, effusion and PDS increased with age, was higher in the right hand than in the left hand and was more common in proximal than in distal hand joints. SH and effusion often occurred in multiple joints (P < 0.001). SH in one joint was strongly associated with presence of SH in the same joint of the opposite hand (odds ratio [OR]= 6.60, 95% confidence interval [CI]: 6.19-7.03) followed by SH in other joints in the same row, (OR=5.70, 95%CI: 5.32-6.11), and then other joints in the same ray of the same hand (OR=1.49, 95%CI: 1.39-1.60). Similar patterns were observed for effusion.

Hand synovial abnormalities are common among older people, often affect multiple hand joints and present a unique pattern. These findings suggest both systemic and mechanical factors play roles in their occurrence.

The mechanisms responsible for the distribution and severity of joint involvement in rheumatoid arthritis (RA) are not known. To explore whether site-specific fibroblast-like synoviocyte (FLS) biology might be associated with location-specific synovitis and explain the predilection for hand (wrist/metacarpal phalangeal joints) involvement in RA, we generated transcriptomic and chromatin accessibility data from FLS to identify the transcription factors and pathways. Networks were constructed by integration of chromatin accessibility and gene expression data. Analysis revealed joint-specific patterns of FLS phenotype, with proliferative, migratory, proinflammatory, and matrix-degrading characteristics observed in resting FLS derived from the hand joints compared with hip or knee. TNF stimulation amplified these differences, with greater enrichment of proinflammatory and proliferative genes in hand FLS compared with hip and knee FLS. Hand FLS also had the greatest expression of markers associated with an "activated" state relative to the "resting" state, with the greatest cytokine and MMP expression in TNF-stimulated hand FLS. Predicted differences in proliferation and migration were biologically validated with hand FLS exhibiting greater migration and cell growth than hip or knee FLS. Distinctive joint-specific FLS biology associated with a more aggressive inflammatory response might contribute to the distribution and severity of joint involvement in RA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to progressive joint damage. Circular RNA (circRNA) can regulate the inflammatory response of fibroblast-like synoviocytes (FLSs) in RA, influencing the disease progression. Paeoniflorin (PF) is the main active ingredient extracted from Paeonia lactiflora and is known for its anti-inflammatory effect. This study aims to explore the potential mechanisms by which hsa_circ_009012 and PF regulate the inflammatory response in RA.

RNA expression of hsa_circ_009012, has-microRNA-1286 (miR-1286), toll-like receptor 4 (TLR4), NOD-like receptor thermal protein domain associated protein 3 (NLRP3) was assessed by real-time quantitative polymerase chain reaction (RT-qPCR) or western blotting (WB). Cell inflammation markers (TNF-α, IL-1β, IL-6) were assessed by RT-qPCR and immunofluorescence (IF). Counting Kit-8 (CCK-8) assay, flow cytometry, and transwell assay were utilized to test cell viability, cell cycle distribution, and migration.

Hsa_circ_009012 was highly expressed in RA-FLS. Hsa_circ_009012 over-expression facilitated the inflammation in RA-FLS and was closely associated with the miR-1286/TLR4 axis. Paeoniflorin inhibited inflammation and the expression of hsa_circ_009012 and TLR4, while upregulating the expression of miR-1286 in RA-FLS. Moreover, the upregulation of hsa_circ_009012 reversed the repressive effect of paeoniflorin on RA-FLS progression.

Paeoniflorin inhibits the inflammation of RA-FLS via mediating the hsa_circ_009012/miR-1286/TLR4/NLRP3 axis.

In rheumatoid arthritis, juvenile idiopathic arthritis and other forms of inflammatory arthritis, the immune system targets certain joints but not others. The pattern of joints affected varies by disease and by individual, with flares most commonly involving joints that were previously inflamed. This phenomenon, termed joint-specific memory, is difficult to explain by systemic immunity alone. Mechanisms of joint-specific memory include the involvement of synovial resident memory T cells that remain in the joint during remission and initiate localized disease recurrence. In addition, arthritis-induced durable changes in synovial fibroblasts and macrophages can amplify inflammation in a site-specific manner. Together with ongoing systemic processes that promote extension of arthritis to new joints, these local factors set the stage for a stepwise progression in disease severity, a paradigm for arthritis chronicity that we term the joint accumulation model. Although durable drug-free remission through early treatment remains elusive for most forms of arthritis, the joint accumulation paradigm defines new therapeutic targets, emphasizes the importance of sustained treatment to prevent disease extension to new joints, and identifies a rolling window of opportunity for altering the natural history of arthritis that extends well beyond the initiation phase of disease.

Huntingtin-interacting protein-1 (HIP1) is a new arthritis severity gene implicated in the regulation of the invasive properties of rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS). These invasive properties of FLS strongly correlate with radiographic and histology damage in patients with RA and rodent models of arthritis. While HIP1 has several intracellular functions, little is known about its binding proteins, and identifying them has the potential to expand our understanding of its role in cell invasion and other disease-contributing phenotypes, and potentially identify new targets for therapy.

FLS cell lines from arthritic DA (highly invasive) and from arthritis-protected congenic rats R6 (minimally invasive), which differ in an amino-acid changing HIP1 SNP, were cultured and lysed, and proteins were immunoprecipitated with an anti-HIP1 antibody. Immunoprecipitates were analyzed by mass spectrometry. Differentially detected (bound) proteins were selected for functional experiments using siRNA knockdown in human RA FLS to examine their effect in cell invasiveness, adhesion, cell migration and proliferation, and immunofluorescence microscopy.

Proteins detected included a few known HIP1-binding proteins and several new ones. Forty-five proteins differed in levels detected in the DA versus R6 congenic mass spectrometry analyses. Thirty-two of these proteins were knocked down and studied in vitro, with 10 inducing significant changes in RA FLS phenotypes. Specifically, knockdown of five HIP1-binding protein genes (CHMP4BL1, COPE, KIF1C, YWHAG, and YWHAH) significantly decreased FLS invasiveness. Knockdown of KIF1C also reduced RA FLS migration. The binding of four selected proteins to human HIP1 was confirmed. KIF1C colocalized with lamellipodia, and its knockdown prevented RA FLS from developing an elongated morphology with thick linearized actin fibers or forming polarized lamellipodia, all required for cell mobility and invasion. Unlike HIP1, KIF1C knockdown did not affect Rac1 signaling.

We have identified new HIP1-binding proteins and demonstrate that 10 of them regulate key FLS phenotypes. These HIP1-binding proteins have the potential to become new therapeutic targets and help better understand the RA FLS pathogenic behavior. KIF1C knockdown recapitulated the morphologic changes previously seen in the absence of HIP1, but did not affect the same cell signaling pathway, suggesting involvement in the regulation of different processes.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and arthritic pain. Sinomenine (SIN), derived from the rhizome of Chinese medical herb Qing Teng (scientific name: Sinomenium acutum (Thunb.) Rehd. Et Wils), has a longstanding use in Chinese traditional medicine for treating rheumatoid arthritis. It has been shown to possess anti-inflammatory, analgesic, and immunosuppressive effects with minimal side-effects clinically. However, the mechanisms governing its effects in treatment of joint pathology, especially on fibroblast-like synoviocytes (FLSs) dysfunction, and arthritic pain remains unclear.

This study aimed to investigate the effect and underlying mechanism of SIN on arthritic joint inflammation and joint FLSs dysfunctions.

Collagen-induced arthritis (CIA) was induced in rats and the therapeutic effects of SIN on joint pathology were evaluated histopathologically. Next, we conducted a series of experiments using LPS-induced FLSs, which were divided into five groups (Naïve, LPS, SIN 10, 20, 50 μg/ml). The expression of inflammatory factors was measured by qPCR and ELISA. The invasive ability of cells was detected by modified Transwell assay and qPCR. Transwell migration and cell scratch assays were used to assess the migration ability of cells. The distribution and content of relevant proteins were observed by immunofluorescence and laser confocal microscopy, as well as Western Blot and qPCR. FLSs were transfected with plasmids (CRMP2 T514A/D) to directly modulate the post-translational modification of CRMP2 protein and downstream effects on FLSs function was monitored.

SIN alleviated joint inflammation in rats with CIA, as evidenced by improvement of synovial hyperplasia, inflammatory cell infiltration and cartilage damage, as well as inhibition of pro-inflammatory cytokines release from FLSs induced by LPS. In vitro studies revealed a concentration-dependent suppression of SIN on the invasion and migration of FLSs induced by LPS. In addition, SIN downregulated the expression of cellular CRMP2 that was induced by LPS in FLSs, but increased its phosphorylation at residue T514. Moreover, regulation of pCRMP2 T514 by plasmids transfection (CRMP2 T514A/D) significantly influenced the migration and invasion of FLSs. Finally, SIN promoted nuclear translocation of pCRMP2 T514 in FLSs.

SIN may exert its anti-inflammatory and analgesic effects by modulating CRMP2 T514 phosphorylation and its nuclear translocation of FLSs, inhibiting pro-inflammatory cytokine release, and suppressing abnormal invasion and migration. Phosphorylation of CRMP2 at the T514 site in FLSs may present a new therapeutic target for treating inflammatory joint's destruction and arthritic pain in RA.

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.

Erythropoietin (EPO) known as an erythrocyte-stimulating factor is increased in patients with rheumatoid arthritis (RA). Nevertheless, the function of EPO in the process of RA and relative mechanism needs to be further clarified.

The level of EPO in serum and synovial fluid from patients with RA and healthy controls was determined by . Collagen-induced arthritis (CIA) mice were constructed to confirm the role of EPO on RA pathogenesis. Differentially expressed genes (DEGs) of EPO-treated fibroblast-like synoviocyte (FLS) were screened by transcriptome sequencing. The transcription factor of neuraminidase 3 (NEU3) of DEGs was verified by double luciferase reporting experiment, DNA pulldown, electrophoretic mobility shift assay and chromatin immunoprecipitation-quantitative PCR (qPCR) assay.

The overexpression of EPO was confirmed in patients with RA, which was positively associated with Disease Activity Score 28-joint count. Additionally, EPO intervention could significantly aggravate the joint destruction in CIA models. The upregulation of NEU3 was screened and verified by transcriptome sequencing and qPCR in EPO-treated FLS, and signal transducer and activator of transcription 5 was screened and verified to be the specific transcription factor of NEU3. EPO upregulates NEU3 expression via activating the Janus kinase 2 (JAK2)-STAT5 signalling pathway through its receptor EPOR, thereby to promote the desialylation through enhancing the migration and invasion ability of FLS, which is verified by JAK2 inhibitor and NEU3 inhibitor.

EPO, as a proinflammatory factor, accelerates the process of RA through transcriptional upregulation of the expression of NEU3 by JAK2/STAT5 pathway.

There is growing evidence of an elevated risk of lung cancer in patients with rheumatoid arthritis. The poor prognosis of rheumatoid arthritis-associated lung cancer and the lack of therapeutic options pose an even greater challenge to the clinical management of patients. This study aimed to identify potential molecular targets associated with the progression of rheumatoid arthritis-associated lung cancer and examine the efficacy of naringenin nanoparticles targeting cyclin B1. Mendelian randomizatio analysis revealed that rheumatoid arthritis has a positive correlation with the risk of lung cancer. Cyclin B1 was significantly upregulated in patients with rheumatoid arthritis-associated lung cancer and was significantly overexpressed in synovial tissue fibroblasts. Furthermore, the overexpression of cyclin B1 in rheumatoid arthritis fibroblast-like synoviocytes, which promotes their proliferation and fibroblast-to-myofibroblast transition, can significantly contribute to the growth and infiltration of lung cancer cells. Importantly, our prepared naringenin nanoparticles targeting cyclin B1 effectively attenuated proliferation and fibroblast-to-myofibroblast transition by blocking cells at the G2/M phase. In vivo experiments, naringenin nanoparticles targeting cyclin B1 significantly alleviated the development of collagen-induced arthritis and lung orthotopic tumors. Collectively, our results reveal that naringenin nanoparticles targeting cyclin B1 can suppress the progression of rheumatoid arthritis-associated lung cancer by inhibiting fibroblast-to-myofibroblast transition. These findings provide new insights into the treatment of rheumatoid arthritis-associated lung cancer therapy.

Cellular and organism survival depends upon the regulation of pH, which is regulated by highly specialized cell membrane transporters, the solute carriers (SLC) (For a comprehensive list of the solute carrier family members, see: https://www.bioparadigms.org/slc/ ). The SLC4 family of bicarbonate (HCO3-) transporters consists of ten members, sorted by their coupling to either sodium (NBCe1, NBCe2, NBCn1, NBCn2, NDCBE), chloride (AE1, AE2, AE3), or borate (BTR1). The ionic coupling of SLC4A9 (AE4) remains controversial. These SLC4 bicarbonate transporters may be controlled by cellular ionic gradients, cellular membrane voltage, and signaling molecules to maintain critical cellular and systemic pH (acid-base) balance. There are profound consequences when blood pH deviates even a small amount outside the normal range (7.35-7.45). Chiefly, Na+-coupled bicarbonate transporters (NCBT) control intracellular pH in nearly every living cell, maintaining the biological pH required for life. Additionally, NCBTs have important roles to regulate cell volume and maintain salt balance as well as absorption and secretion of acid-base equivalents. Due to their varied tissue expression, NCBTs have roles in pathophysiology, which become apparent in physiologic responses when their expression is reduced or genetically deleted. Variations in physiological pH are seen in a wide variety of conditions, from canonically acid-base related conditions to pathologies not necessarily associated with acid-base dysfunction such as cancer, glaucoma, or various neurological diseases. The membranous location of the SLC4 transporters as well as recent advances in discovering their structural biology makes them accessible and attractive as a druggable target in a disease context. The role of sodium-coupled bicarbonate transporters in such a large array of conditions illustrates the potential of treating a wide range of disease states by modifying function of these transporters, whether that be through inhibition or enhancement.

Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.

Fibroblast-like synoviocytes (FLS) are important components of the synovial membrane. They can contribute to joint damage through crosstalk with inflammatory cells and direct actions on tissue damage pathways in rheumatoid arthritis (RA). Recent evidence suggests that, compared with FLS in normal synovial tissue, FLS in RA synovial tissue exhibits significant differences in metabolism. Recent metabolomic studies have demonstrated that metabolic changes, including those in glucose, lipid, and amino acid metabolism, exist before synovitis onset. These changes may be a result of increased biosynthesis and energy requirements during the early phases of the disease. Activated T cells and some cytokines contribute to the conversion of FLS into cells with metabolic abnormalities and pro-inflammatory phenotypes. This conversion may be one of the potential mechanisms behind altered FLS metabolism. Targeting metabolism can inhibit FLS proliferation, providing relief to patients with RA. In this review, we aimed to summarize the evidence of metabolic changes in FLS in RA, analyze the mechanisms of these metabolic alterations, and assess their effect on RA phenotype. Finally, we aimed to summarize the advances and challenges faced in targeting FLS metabolism as a promising therapeutic strategy for RA in the future.