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F1000Research 2023Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall... (Randomized Controlled Trial)
Randomized Controlled Trial
Role of specialized pro-resolving mediators on inflammation, cardiometabolic health, disease progression, and quality of life after omega-3 PUFA supplementation and aerobic exercise training in individuals with rheumatoid arthritis: a randomized 16-week, placebo-controlled interventional trial.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by autoantibody production and synovial membrane damage. It significantly impairs overall function and quality of life. Consumption of omega-3 (n-3) polyunsaturated fatty acids (PUFAs) and regular aerobic exercise (AEx) training are reported to have positive effects on the progression of RA. However, the mechanisms behind these benefits are still inconclusive. This study protocol will investigate the effects of n-3 PUFA supplementation and AEx training on disease progression, cardiometabolic health, and quality of life, and their association with the plasma and synovial fluid levels of specialized pro-resolving mediators (SPMs) in subjects with RA. The study consists of a 16-week intervention period, during which participants will be randomly assigned in a double-blinded manner to one of four groups: placebo control (PLA), PLA+AEx, n-3, or n-3+AEx. The PLA groups will be given a gelatin-filled capsule, while the n-3 groups will be given n-3 PUFAs equivalent to 2.5 g/d of docosahexaenoic acid and 0.5 g/d of eicosapentaenoic acid. The AEx groups will perform exercise three times per week on a stationary electronically braked cycle ergometer at 60-70% of their VO2peak for 50-60 minutes. Before and after the intervention, participants will undergo RA-specific and functional measurements, peak aerobic capacity test, and a dietary and physical activity assessment. Venous blood and synovial fluid from the knee joint will be collected. Changes in disease progression, cardiometabolic health, and quality of life, as well as erythrocyte membrane composition to assess n-3 incorporation, SPM levels, inflammatory markers, and gene expression from blood and synovial fluid will be analyzed. The study aims to elucidate the SPMs that regulate the inflammatory gene expression pathways and associate them with the improvements in disease progression, cardiometabolic health, and quality of life after n-3 PUFA supplementation and AEx training. : ClinicalTrials.gov #NCT05945693.
Topics: Humans; Arthritis, Rheumatoid; Fatty Acids, Omega-3; Quality of Life; Dietary Supplements; Disease Progression; Exercise; Inflammation; Double-Blind Method; Male; Female; Middle Aged; Adult
PubMed: 38778807
DOI: 10.12688/f1000research.138392.1 -
Pharmacological Research Jul 2024Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting...
INTRODUCTION
Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed.
OBJECTIVES
To explore the role of Midline-1 (Mid1) in synovial activation.
METHODS
NOD.Cg-Prkdc Il2rg/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1, Dpp4, and Mid1Dpp4 mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status.
RESULTS
An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis.
CONCLUSION
Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.
Topics: Animals; Arthritis, Rheumatoid; Humans; Dipeptidyl Peptidase 4; Arthritis, Experimental; Ubiquitin-Protein Ligases; Mice, Inbred C57BL; Mice; Synovitis; Protein Processing, Post-Translational; Mice, Knockout; Ubiquitination; Ubiquitin; Mice, Inbred NOD; Synovial Membrane; Male; Cell Proliferation; Transcription Factors; Synoviocytes
PubMed: 38777113
DOI: 10.1016/j.phrs.2024.107224 -
PloS One 2024To elucidate potential molecular mechanisms differentiating osteoarthritis (OA) and rheumatoid arthritis (RA) through a bioinformatics analysis of differentially...
OBJECTIVE
To elucidate potential molecular mechanisms differentiating osteoarthritis (OA) and rheumatoid arthritis (RA) through a bioinformatics analysis of differentially expressed genes (DEGs) in patient synovial cells, aiming to provide new insights for clinical treatment strategies.
MATERIALS AND METHODS
Gene expression datasets GSE1919, GSE82107, and GSE77298 were downloaded from the Gene Expression Omnibus (GEO) database to serve as the training groups, with GSE55235 being used as the validation dataset. The OA and RA data from the GSE1919 dataset were merged with the standardized data from GSE82107 and GSE77298, followed by batch effect removal to obtain the merged datasets of differential expressed genes (DEGs) for OA and RA. Intersection analysis was conducted on the DEGs between the two conditions to identify commonly upregulated and downregulated DEGs. Enrichment analysis was then performed on these common co-expressed DEGs, and a protein-protein interaction (PPI) network was constructed to identify hub genes. These hub genes were further analyzed using the GENEMANIA online platform and subjected to enrichment analysis. Subsequent validation analysis was conducted using the GSE55235 dataset.
RESULTS
The analysis of differentially expressed genes in the synovial cells from patients with Osteoarthritis (OA) and Rheumatoid Arthritis (RA), compared to a control group (individuals without OA or RA), revealed significant changes in gene expression patterns. Specifically, the genes APOD, FASN, and SCD were observed to have lower expression levels in the synovial cells of both OA and RA patients, indicating downregulation within the pathological context of these diseases. In contrast, the SDC1 gene was found to be upregulated, displaying higher expression levels in the synovial cells of OA and RA patients compared to normal controls.Additionally, a noteworthy observation was the downregulation of the transcription factor PPARG in the synovial cells of patients with OA and RA. The decrease in expression levels of PPARG further validates the alteration in lipid metabolism and inflammatory processes associated with the pathogenesis of OA and RA. These findings underscore the significance of these genes and the transcription factor not only as biomarkers for differential diagnosis between OA and RA but also as potential targets for therapeutic interventions aimed at modulating their expression to counteract disease progression.
CONCLUSION
The outcomes of this investigation reveal the existence of potentially shared molecular mechanisms within Osteoarthritis (OA) and Rheumatoid Arthritis (RA). The identification of APOD, FASN, SDC1, TNFSF11 as key target genes, along with their downstream transcription factor PPARG, highlights common potential factors implicated in both diseases. A deeper examination and exploration of these findings could pave the way for new candidate targets and directions in therapeutic research aimed at treating both OA and RA. This study underscores the significance of leveraging bioinformatics approaches to unravel complex disease mechanisms, offering a promising avenue for the development of more effective and targeted treatments.
Topics: Arthritis, Rheumatoid; Humans; Osteoarthritis; Gene Expression Profiling; Protein Interaction Maps; Synovial Membrane; Computational Biology; Gene Regulatory Networks; Gene Expression Regulation; Databases, Genetic
PubMed: 38771826
DOI: 10.1371/journal.pone.0303506 -
Molecular Biotechnology May 2024The occurrence of osteoarthritis in the knee joint is regulated by a complex network, and there is currently no specific therapeutic drug available. Functional exercises...
The occurrence of osteoarthritis in the knee joint is regulated by a complex network, and there is currently no specific therapeutic drug available. Functional exercises and treatments targeting inflammatory factors have shown the potential to alleviate knee osteoarthritis to some extent. Therefore, the aim of this study was to assess the intra-articular injection (IAI) of autologous platelet-rich plasma (PRP) combined with physical therapy (PT) in treating knee osteoarthritis. A total of 128 patients with knee osteoarthritis were included in the study, including 64 males and 64 females. A total of 128 patients were divided into sodium hyaluronate group (HA group), PRP group, PRP + PT group, and PT group, with 32 cases in each group. Visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and Japanese Orthopaedic Association (JOA) were employed to evaluate the recovery of patients from pain and osteoarthritis. Color Doppler ultrasound imaging technology was utilized to assess joint effusion, synovial membrane thickness, and articular cartilage thickness in patients with knee osteoarthritis. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1), and matrix metallopeptidase 3 (MMP-3) in the synovial fluid. Compared to the HA group, the PT group, PRP group, and PRP combined with PT (PRP + PT) group all showed reduced VAS and WOMAC scores, increased JOA scores, decreased joint effusion, synovial membrane thickness, and articular cartilage thickness in the knee joint. Additionally, levels of IL-1β and MMP-3 in the synovial fluid decreased, while TGF-β1 levels increased (P < 0.05). Compared with the PT group, the VAS and WOMAC scores of the knee joint in the PRP group decreased, JOA scores increased, joint effusion, synovial thickness, and articular cartilage thickness decreased, but there was no statistically significant difference (P > 0.05), and the PRP + PT group showed decreased VAS and WOMAC scores, increased JOA scores, reduced joint effusion, synovial membrane thickness, and articular cartilage thickness in the knee joint. Moreover, levels of IL-1β and MMP-3 in the synovial fluid decreased, while TGF-β1 levels increased (P < 0.05). No severe adverse reactions were observed in any of the four groups, but the pain rate in the PRP + TP group was significantly lower than PT group, PRP group, and PRP + PT group (P < 0.05). The efficacy of intra-articular injection of PRP combined with exercise therapy in the treatment of knee osteoarthritis is superior to that of single interventions such as simple interventions of HA, PRP injection, and PT. Furthermore, intra-articular injection of PRP combined with exercise therapy demonstrates enhanced effectiveness in improving the inflammatory levels associated with knee osteoarthritis and facilitating the rehabilitation process.
PubMed: 38771422
DOI: 10.1007/s12033-024-01177-8 -
Journal of Nanobiotechnology May 2024Osteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone...
BACKGROUND AND AIMS
Osteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone hyperplasia. The synovial tissue plays a pivotal role in cartilage regulation. Exosomes (EXOs), small membrane-bound vesicles released by cells into the extracellular space, are crucial in mediating intercellular communication and facilitating the exchange of information between tissues. Our study aimed to devise a hydrogel microsphere infused with SOD3-enriched exosomes (S-EXOs) to protect cartilage and introduce a novel, effective approach for OA treatment.
MATERIALS AND METHODS
We analyzed single-cell sequencing data from 4247 cells obtained from the GEO database. Techniques such as PCR, Western Blot, immunofluorescence (IF), and assays to measure oxidative stress levels were employed to validate the cartilage-protective properties of the identified key protein, SOD3. In vivo, OA mice received intra-articular injections of S-EXOs bearing hydrogel microspheres, and the effectiveness was assessed using safranine O (S.O) staining and IF.
RESULTS
Single-cell sequencing data analysis suggested that the synovium influences cartilage via the exocrine release of SOD3. Our findings revealed that purified S-EXOs enhanced antioxidant capacity of chondrocytes, and maintained extracellular matrix metabolism stability. The S-EXO group showed a significant reduction in mitoROS and ROS levels by 164.2% (P < 0.0001) and 142.7% (P < 0.0001), respectively, compared to the IL-1β group. Furthermore, the S-EXO group exhibited increased COL II and ACAN levels, with increments of 2.1-fold (P < 0.0001) and 3.1-fold (P < 0.0001), respectively, over the IL-1β group. Additionally, the S-EXO group showed a decrease in MMP13 and ADAMTS5 protein expression by 42.3% (P < 0.0001) and 44.4% (P < 0.0001), respectively. It was found that S-EXO-containing hydrogel microspheres could effectively deliver SOD3 to cartilage and significantly mitigate OA progression. The OARSI score in the S-EXO microsphere group markedly decreased (P < 0.0001) compared to the OA group.
CONCLUSION
The study demonstrated that the S-EXOs secreted by synovial fibroblasts exert a protective effect on chondrocytes, and microspheres laden with S-EXOs offer a promising therapeutic alternative for OA treatment.
Topics: Animals; Osteoarthritis; Exosomes; Mice; Oxidative Stress; Chondrocytes; Humans; Superoxide Dismutase; Synovial Membrane; Male; Disease Progression; Nanoparticles; Mice, Inbred C57BL; Hydrogels; Microspheres; Cartilage, Articular; Extracellular Matrix
PubMed: 38769545
DOI: 10.1186/s12951-024-02538-w -
Scandinavian Journal of Clinical and... May 2024PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27...
PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA ( = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA ( = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients ( = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) ( < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.
Topics: Humans; Arthritis, Psoriatic; Arthritis, Rheumatoid; Synovial Fluid; Autoantibodies; Male; Middle Aged; Female; Adult; Aged; Case-Control Studies; Osteoarthritis; Enzyme-Linked Immunosorbent Assay
PubMed: 38767606
DOI: 10.1080/00365513.2024.2352844 -
Journal of Dental Research Jul 2024Inflammation and loss of articular cartilage are considered the major cause of temporomandibular joint osteoarthritis (TMJOA), a painful condition of the...
Inflammation and loss of articular cartilage are considered the major cause of temporomandibular joint osteoarthritis (TMJOA), a painful condition of the temporomandibular joint (TMJ). To determine the cause of TMJ osteoarthritis in these patients, synovial fluid of TMJOA patients was compared prior to and after hyaluronic lavage, revealing substantially elevated levels of interleukin (IL) 1β, reactive oxidative stress (ROS), and an overload of Fe and Fe prior to lavage, indicative of ferroptosis as a mode of chondrocyte cell death. To ask whether prolonged inflammatory conditions resulted in ferroptosis-like transformation in vitro, we subjected TMJ chondrocytes to IL-1β treatment, resulting in a shift in messenger RNA sequencing gene ontologies related to iron homeostasis and oxidative stress-related cell death. Exposure to rat unilateral anterior crossbite conditions resulted in reduced COL2A1 expression, fewer chondrocytes, glutathione peroxidase 4 (GPX4) downregulation, and 4-hydroxynonenal (4-HNE) upregulation, an effect that was reversed after intra-articular injections of the ferroptosis inhibitor ferrostatin 1 (Fer-1). Our study demonstrated that ferroptosis conditions affected mitochondrial structure and function, while the inhibitor Fer-1 restored mitochondrial structure and the inhibition of hypoxia-inducible factor 1α (HIF-1α) or the transferrin receptor 1 (TFRC) rescued IL-1β-induced loss of mitochondrial membrane potential. Inhibition of HIF-1α downregulated IL-1β-induced TFRC expression, while inhibition of TFRC did not downregulate IL-1β-induced HIF-1α expression in chondrocytes. Moreover, inhibition of HIF-1α or TFRC downregulated the IL-1β-induced MMP13 expression in chondrocytes, while inhibition of HIF-1α or TFRC rescued IL-1β-inhibited COL2A1 expression in chondrocytes. Furthermore, upregulation of TFRC promoted Fe entry into chondrocytes, inducing the Fenton reaction and lipid peroxidation, which in turn caused ferroptosis, a disruption in chondrocyte functions, and an exacerbation of condylar cartilage degeneration. Together, these findings illustrate the far-reaching effects of chondrocyte ferroptosis in TMJOA as a mechanism causing chondrocyte death through iron overload, oxidative stress, and articular cartilage degeneration and a potential major cause of TMJOA.
Topics: Chondrocytes; Ferroptosis; Animals; Hypoxia-Inducible Factor 1, alpha Subunit; Rats; Receptors, Transferrin; Osteoarthritis; Interleukin-1beta; Oxidative Stress; Temporomandibular Joint Disorders; Male; Humans; Rats, Sprague-Dawley; Inflammation; Phospholipid Hydroperoxide Glutathione Peroxidase; Temporomandibular Joint; Cyclohexylamines; Cartilage, Articular; Collagen Type II; Reactive Oxygen Species; Female; Aldehydes; Phenylenediamines
PubMed: 38766865
DOI: 10.1177/00220345241242389 -
Journal of Orthopaedics and... May 2024Total joint arthroplasty is the recommended treatment for patients with end-stage osteoarthritis, as it reduces disability and pain and restores joint function. However,... (Review)
Review
Total joint arthroplasty is the recommended treatment for patients with end-stage osteoarthritis, as it reduces disability and pain and restores joint function. However, prosthetic joint infection is a serious complication of this procedure, with the two-stage exchange being the most common treatment method. While there is consensus on diagnosing prosthetic joint infection, there is a lack of agreement on the parameters that can guide the surgeon in performing definitive reimplantation in a two-stage procedure. One approach that has been suggested to improve the accuracy of microbiologic investigations before definitive reimplantation is to observe a holiday period from antibiotic therapy to improve the accuracy of cultures from periprosthetic tissues, but these cultures report some degree of aspecificity. Therefore, several pieces of evidence highlight that performing reimplantation using continuous antibiotic therapy should be considered a safe and effective approach, leading to higher cure rates and a shorter period of disability. Dosage of C-reactive protein (CRP), erythrocyte sedimentation rate (ERS) and D-dimer are helpful in diagnosing prosthetic joint infection, but only D-dimer has shown sufficient accuracy in predicting the risk of infection recurrence after a two-stage procedure. Synovial fluid analysis before reimplantation has been shown to be the most accurate in predicting recurrence, and new cutoff values for leukocyte count and neutrophil percentage have shown a useful predictive rule to identify patients at risk of unfavourable outcome. A new scoring system based on a numerical score calculated from the beta coefficient derived through multivariate analysis of D-dimer levels, synovial fluid leukocytes and relative neutrophils percentage has demonstrated high accuracy when it comes to guiding the second step of two-stage procedure. In conclusion, reimplantation may be a suitable option for patients who are on continuous therapy without local symptoms, and with CRP and ERS within the normal range, with low synovial fluid leukocytes (< 952/mL) and a low relative neutrophil percentage (< 52%) and D-dimer below 1100 µg/mL. A numerical score derived from analysing these three parameters can serve as a valuable tool in determining the feasibility of reimplantation in these patients.
Topics: Humans; Prosthesis-Related Infections; Reoperation; Anti-Bacterial Agents; Arthroplasty, Replacement; C-Reactive Protein; Fibrin Fibrinogen Degradation Products; Blood Sedimentation; Synovial Fluid
PubMed: 38761247
DOI: 10.1186/s10195-024-00767-1 -
Clinical Rheumatology Jul 2024
Topics: Humans; Arthritis, Rheumatoid; Synovial Fluid; Cytokines; T Follicular Helper Cells; T-Lymphocytes, Helper-Inducer
PubMed: 38761245
DOI: 10.1007/s10067-024-07006-2 -
Redox Biology Jul 2024Our previous studies have shown that lipoxin A (LXA) can serve as a potential biomarker for assessing the efficacy of exercise therapy in knee osteoarthritis (KOA), and...
Lipoxin A ameliorates knee osteoarthritis progression in rats by antagonizing ferroptosis through activation of the ESR2/LPAR3/Nrf2 axis in synovial fibroblast-like synoviocytes.
BACKGROUND
Our previous studies have shown that lipoxin A (LXA) can serve as a potential biomarker for assessing the efficacy of exercise therapy in knee osteoarthritis (KOA), and fibroblast-like synoviocytes (FLSs) may play a crucial role in KOA pain as well as in the progression of the pathology.
OBJECTIVE
By analyzing the GSE29746 dataset and collecting synovial samples from patients with different Kellgren-Lawrence (KL) grades for validation, we focused on exploring the potential effect of LXA on ferroptosis in FLSs through the ESR2/LPAR3/Nrf2 axis to alleviate pain and pathological advancement in KOA.
METHODS
The association between FLSs ferroptosis and chondrocyte matrix degradation was explored by cell co-culture. We overexpressed and knocked down LPAR3 in vitro to explore its potential mechanism in FLSs. A rat model of monosodium iodoacetate (MIA)-induced KOA was constructed and intervened with moderate-intensity treadmill exercise and intraperitoneal injection of PHTPP to investigate the effects of the LXA intracellular receptor ESR2 on exercise therapy.
RESULTS
ESR2, LPAR3, and GPX4 levels in the synovium decreased with increasing KL grade. After LXA intervention in the co-culture system, GPX4, LPAR3, and ESR2 were upregulated in FLSs, collagen II was upregulated in chondrocytes, and MMP3 and ADAM9 were downregulated. LPAR3 overexpression upregulated the expression of GPX4, Nrf2, and SOD1 in FLSs, while downregulating the expression of MMP13 and MMP3; LPAR3 knockdown reversed these changes. Moderate-intensity platform training improved the behavioral manifestations of pain in KOA rats, whereas PHTPP treatment partially reversed the improvement in synovial and cartilage pathologies induced by platform training.
CONCLUSION
LXA inhibited FLSs ferroptosis by activating the ESR2/LPAR3/Nrf2 axis, thereby alleviating the pain and pathological progression of KOA. This study brings a new target for the treatment of KOA and also leads to a deeper understanding of the potential mechanisms of exercise therapy for KOA.
Topics: Animals; Osteoarthritis, Knee; Rats; Ferroptosis; Lipoxins; NF-E2-Related Factor 2; Synoviocytes; Humans; Male; Disease Models, Animal; Fibroblasts; Signal Transduction; Rats, Sprague-Dawley; Synovial Membrane; Disease Progression
PubMed: 38754271
DOI: 10.1016/j.redox.2024.103143