Successful Treatment of Ultrasound-confirmed Synovitis in Anti-MDA5 Antibody-positive Clinically Amyopathic Dermatomyositis with Corticosteroid Therapy.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive clinically amyopathic dermatomyositis (CADM) is a subtype of dermatomyositis without severe myositis but with characteristic cutaneous manifestations and severe interstitial lung disease. Joint symptoms can occur in patients with anti-MDA5 antibody-positive CADM. However, the treatment strategy and utility of ultrasound for treating joint symptoms remain unknown. We herein report an 85-year-old man with anti-MDA5 antibody-positive CADM who presented with ultrasound-confirmed synovitis that improved with medium-dose corticosteroid therapy.

Correlation of meniscus tear type with synovial inflammation and the therapeutic potential of docosapentaenoic acid.

BACKGROUND: Synovitis, characterized by inflammation of the synovial membrane, is commonly induced by meniscus tears. However, significant differences in inflammatory responses and the key inflammatory mediators of synovium induced by different types of meniscal tears remain unclear. METHODS: Magnetic resonance imaging (MRI) was employed to identify the type of meniscus tear, and the quantification of synovial inflammation was assessed through H&E staining assay. Transcription and expression levels of IL-1ß and IL-6 were evaluated using bioinformatics, ELISA, RT-qPCR, and IHC of CD68 staining assays. The therapeutic potential of Docosapentaenoic Acid (DPA) was determined through network pharmacology, ELISA, and RT-qPCR assays. The safety of DPA was assessed using colony formation and EdU staining assays. RESULTS: The results indicate that both IL-1ß and IL-6 play pivotal roles in synovitis pathogenesis, with distinct expression levels across various subtypes. Among tested meniscus tears, oblique tear and bucket handle tear induced the most severe inflammation, followed by radial tear and longitudinal tear, while horizontal tear resulted in the least inflammation. Furthermore, in synovial inflammation induced by specific meniscus tears, the anterior medial tissues exhibited significantly higher local inflammation than the anterior lateral and suprapatellar regions, highlighting the clinical relevance and practical guidance of anterior medial tissues' inflammatory levels. Additionally, we identified the essential omega-3 fatty acid DPA as a potential therapeutic agent for synovitis, demonstrating efficacy in blocking the transcription and expression of IL-1ß and IL-6 with minimal side effects. CONCLUSION: These findings provide valuable insights into the nuanced nature of synovial inflammation induced by various meniscal tear classifications and contribute to the development of new adjunctive therapeutic agents in the management of synovitis.

Common Comorbidities in Patients with Remitting Seronegative and Symmetrical Synovitis with Pitting Edema (RS3PE).

OBJECTIVES: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is considered a rare inflammatory rheumatologic disorder that is seen primarily in older adult men. Patients present with arthralgias of large joints accompanied by painful pitting edema of the hands and feet. Few studies have reported the prevalence of metabolic syndromes, including diabetes mellitus and hyperlipidemia in these patients. METHODS: This case series reviewed 25 patients who were diagnosed as having RS3PE in a private outpatient clinic. RESULTS: Nearly half of the patients (48%) had diabetes mellitus, predominantly type 2, and more than half of the patients (60%) had hyperlipidemia. CONCLUSIONS: We believe that future case studies on RS3PE should include an assessment of various comorbidities that can be seen in patients with this autoinflammatory disorder. The increased availability of musculoskeletal ultrasound provides a potential area of study to differentiate this disorder from other inflammatory arthritis and improve reaching the correct diagnosis.

MRI of shoulder girdle in polymyalgia rheumatica: inflammatory findings and their diagnostic value.

BACKGROUND: Non-synovial inflammation as detected by MRI is characteristic in polymyalgia rheumatica (PMR) with potentially high diagnostic value. OBJECTIVE: The objective is to describe inflammatory MRI findings in the shoulder girdle of patients with PMR and discriminate from other causes of shoulder girdle pain. METHODS: Retrospective study of 496 contrast-enhanced MRI scans of the shoulder girdle from 122 PMR patients and 374 non-PMR cases. Two radiologists blinded to clinical and demographic information evaluated inflammation at six non-synovial plus three synovial sites for the presence or absence of inflammation. The prevalence of synovial and non-synovial inflammation, both alone and together with clinical information, was tested for its ability to differentiate PMR from non-PMR. RESULTS: A high prevalence of non-synovial inflammation was identified as striking imaging finding in PMR, in average 3.4±1.7, mean (M)±SD, out of the six predefined sites were inflamed compared with 1.1±1.4 (M±SD) in non-PMR group, p<0.001, with excellent discriminatory effect between PMR patients and non-PMR cases. The prevalence of synovitis also differed significantly between PMR patients and non-PMR cases, 2.5±0.8 (M±SD) vs 1.9±1.1 (M±SD) out of three predefined synovial sites, but with an inferior discriminatory effect. The detection of inflammation at three out of six predefined non-synovial sites differentiated PMR patients from controls with a sensitivity/specificity of 73.8%/85.8% and overall better performance than detection of synovitis alone (sensitivity/specificity of 86.1%/36.1%, respectively). CONCLUSION: Contrast-enhanced MRI of the shoulder girdle is a reliable imaging tool with significant diagnostic value in the assessment of patients suffering from PMR and differentiation to other conditions for shoulder girdle pain.

Effect of weight loss on knee joint synovitis over 48 months and mediation by subcutaneous fat around the knee: data from the Osteoarthritis Initiative.

BACKGROUND: Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. METHODS: We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (< ± 3% change, n = 117) over 48 months matched for age and sex. In magnetic resonance imaging (MRI) at baseline and 48 months, effusion-synovitis and Hoffa-synovitis using the MRI Osteoarthritis Knee Score (MOAKS) and average joint-adjacent SCF (ajSCF) were assessed. Odds-ratios (ORs) for synovitis progression over 48 months (≥ 1 score increase) were calculated in logistic regression models adjusting for age, sex, baseline BMI, Physical Activity Scale for the Elderly (PASE), and baseline SCF measurements. Mediation of the effect of weight loss on synovitis progression by local SCF change was assessed. RESULTS: Odds for effusion-synovitis progression decreased with weight loss and ajSCF decrease (odds ratio [OR] = 0.61 and 0.56 per standard deviation [SD] change, 95% confidence interval [CI] 0.44, 0.83 and 0.40, 0.79, p = 0.002 and 0.001, respectively), whereas odds for Hoffa-synovitis progression increased with weight loss and ajSCF decrease (OR = 1.47 and 1.48, CI 1.05, 2.04 and 1.02, 2.13, p = 0.024 and 0.038, respectively). AjSCF decrease mediated 39% of the effect of weight loss on effusion-synovitis progression. CONCLUSIONS: Effusion-synovitis progression was slowed by weight loss and decrease in local subcutaneous fat. Hoffa-synovitis characterized by fluid in the infrapatellar fat pad increased at the same time, suggesting a decreasing fat pad rather than active synovitis. Decrease in local subcutaneous fat partially mediated the systemic effect of weight loss on synovitis.

Blau Syndrome With Delayed Cutaneous Manifestations: A Case Report.

ABSTRACT: Blau syndrome is a rare familial autoinflammatory disorder characterized by the triad of granulomatous dermatitis, polyarthritis, and uveitis. Blau syndrome exhibits an autosomal dominant inheritance pattern and can be caused by a gain-of-function mutation in nucleotide-binding oligomerization domain 2 (NOD2), a member of the NOD-like receptor family of pattern recognition receptors. Mutations in NOD2 cause upregulation of inflammatory cytokines and resultant autoinflammation. Because of the rarity of this condition and early onset of symptoms, Blau syndrome may be misdiagnosed as juvenile idiopathic arthritis. We present a case of a 37-year-old male patient with a long-documented history of juvenile idiopathic arthritis and uveitis, who developed an asymptomatic eruption of pink papules on the trunk and upper extremities. A biopsy demonstrated noncaseating, well-formed dermal granulomas with relatively sparse lymphocytic inflammation and Langerhans-type giant cells. Genetic testing confirmed a mutation in NOD2. Based on the patient's clinical history, histologic findings, genetic testing, the diagnosis of Blau syndrome was made.

Prevalence of spondyloarthritis in inflammatory bowel disease according ASAS and ultrassonography and its correlation with plasma calprotectin.

BACKGROUND: Enteropathic spondyloarthritis is underdiagnosed and inflammatory biomarkers and ultrasonography (US) could be useful for screening inflammatory bowel disease (IBD) patients. The objective of this study was to evaluate the prevalence of spondyloarthritis (SpA) in IBD patients, according to the Assessment of SpondyloArthritis International Society (ASAS) criteria and the correlation of results of US of entheses and joints with plasma calprotectin levels. METHODS: This was an observational cross-sectional study. Patients from the IBD outpatient clinic of a reference center were evaluated according to ASAS criteria classification, results of US of entheses and joints, and inflammatory biomarker measurements (erythrocyte sedimentation rates, C-reactive protein levels, fecal and plasma calprotectin levels). A p value lower than 0.05 was considered significant. RESULTS: A total of 30.5% of the studied sample (n = 118) of patients with IBD presented at least one inflammatory musculoskeletal manifestation. The overall prevalence of enteropathic SpA was 13.55%, with 10.16% axial SpA and 4.23% peripheral SpA according to the ASAS criteria. A total of 42.1% of patients had an MASEI score greater than 18, 35.2% had synovitis, and 14.7% had tenosynovitis on US, increasing the frequency of diagnosis of enteropathic SpA to 22.8%. Plasma calprotectin levels were similar to those in healthy controls, and correlated only with the fecal calprotectin level (p 0.041). CONCLUSIONS: A total of 13.5% of patients met the criteria in accordance with the ASAS criteria for enteropathic SpA, which increased to 22.8% with the addition of US. The prevalence of enthesitis, synovitis and tenosynovitis by US of symptomatic joints and entheses were 42%, 35% and 14.7% respectively. Plasma calprotectin was correlated with fecal calprotectin but not with inflammatory biomarkers or US or ASAS criteria.

Syndecans, Exostosins and Sulfotransferases as Potential Synovial Inflammation Moderators in Patients with Hip Osteoarthritis.

The gradual deterioration of articular cartilage was thought to be the central event in osteoarthritis (OA), but recent studies demonstrated the importance of low-grade synovitis in the progression of OA. The Syndecan (SDC) family of membrane proteoglycans is known to be involved in the regulation of inflammation, but there is limited evidence considering the role of syndecans in OA synovitis. Our study aimed to investigate the hip OA synovial membrane expression patterns of SDC1, SDC2 and SDC4, as well as exostosins and sulfotransferases (enzymes involved in the polymerisation and modification of syndecans' heparan sulphate chains). Synovial membrane samples of patients with OA (24) were divided into two groups according to their Krenn synovitis score severity. The immunohistochemical expressions of SDC1, SDC2, SDC4, EXT1, EXT2, NDST1 and NDST2 in synovial intima and subintima were then analysed and compared with the control group (patients with femoral neck fracture). According to our study, the immunoexpression of SDC1, NDST1 and EXT2 is significantly increased in the intimal cells of OA synovial membrane in patients with lower histological synovitis scores and SDC4 in patients with higher synovitis scores, in comparison with non-OA controls. The difference in the expression of SDC2 among the OA and non-OA groups was insignificant. SDC1, SDC4, NDST1 and EXT2 seem to be involved as inflammation moderators in low-grade OA synovitis and, therefore, should be further investigated as potential markers of disease progression and therapeutic goals.

Measuring synovial thickness on knee MRI in pediatric patients with arthritis: is contrast necessary?

BACKGROUND: The use of contrast-enhanced imaging has long been standard for magnetic resonance imaging (MRI) assessments of synovitis in juvenile idiopathic arthritis (JIA). However, advancements in MRI technology have allowed for reliable identification of synovium without contrast. OBJECTIVE: To assess the equivalence of unenhanced MRI with contrast-enhanced MRI in evaluating synovial thickness. MATERIALS AND METHODS: This is an institutional review board approved, retrospective study performed in a tertiary children's hospital. Pediatric JIA patients under 21 years old were included who underwent knee MRI scans (1.5 T or 3 T) without and with contrast between January 2012 and January 2022. Two radiologists independently measured synovial thickness at 6 knee sites on contrast-enhanced and unenhanced sequences. Numerical measurements and ordinal scores based on juvenile idiopathic arthritis magnetic resonance imaging scoring (JAMRIS) system were recorded, and tests of equivalence were conducted, as well as between-reader and within-reader reliability by concordance correlation coefficient (CCC). All tests were considered significant at the 5% level. RESULTS: A total of 38 studies from 35 patients (25 females, median age 14 years; interquartile range 7 to 15.7) were included. Equivalence was demonstrated at each of the 6 sites for both continuous measurements (P-values < 0.05) and ordinal scores (P-values < 0.05) based on the average over readers. Within-reader reliability was moderate to high (CCC 0.50-0.89), except for the cruciate ligaments site. Averaged over the 6 sites, reliability between readers was low for unenhanced (CCC 0.47, with 95% CI: [0.41, 0.53]) and moderate for contrast-enhanced (CCC 0.64, with 95% CI: [0.59, 0.69]) sequences. CONCLUSION: Unenhanced knee MRI is equivalent to contrast-enhanced MRI in assessment of synovial thickness using conventional MRI sequences. Contrast material helped improve inter-reader reliability.

IDN5706 Inhibits Synovial Inflammation via Inducing M2 Polarization of Synovial Macrophages in Osteoarthritis Rats.

INTRODUCTION: IDN5706 is a tetrahydro derivative of hyperforin. In this study, we aimed to explore the effect of IDN5706 on synovial macrophages in osteoarthritis (OA) rats and the underlying mechanisms. METHODS: OA rats were employed for the in vivo experiments, and RAW264.7 cells were employed for the in vitro experiments. Histopathological changes in synovium were examined using hematoxylin-eosin staining. Cell apoptosis in synovium was assessed by TUNEL staining. Macrophage polarization was determined by immunohistochemical analysis and flow cytometry. The mRNA expression and protein level of genes were detected by qRT-PCR and Western blot. The efferocytosis of macrophages was assessed by flow cytometry. RESULTS: IDN5706 reversed the increased CD86-positive cells (M1 macrophages) and decreased CD206-positive cells (M2 macrophages), both in synovium and synovial fluid of OA rats. The in vitro experiments further confirmed the promotion effect of IDN5706 on M2 macrophages, accompanied by the elevated Arg-1 and reduced iNOS. Also, the upregulated p-mTOR in synovium and synovial fluid of OA rats were reversed by IDN5706, and the decreased M1 macrophages and increased M2 macrophages induced by IDN5706 were reversed by the mTOR activator. IDN5706 enhanced the efferocytosis of IL-4-treated RAW264.7 cells, and the animal experiments further revealed the involvement of efferocytosis in the improvement of OA by IDN5706. CONCLUSIONS: IDN5706 enhanced the efferocytosis of synovial macrophages by inducing M2 polarization via inhibiting p-mTOR, thus suppressing synovial inflammation and OA development, providing a theoretical basis for IDN5706 as a clinical drug for inflammatory diseases.

Correlation of US-7 and US-9 Scores with Disease Activity Score using 28 Joint Counts (DAS28) in Patients with Rheumatoid Arthritis.

Background: The attentive management of rheumatoid arthritis (RA) has attracted particular attention. The German 7-joint Ultrasound (US-7) is the first scoring system that combines bone erosions and soft tissue lesions in a single composite scoring system. This study aimed to assess the correlation between US-7 and Disease Activity Score Using 28 Joint Counts (DAS28) in clinically active RA patients. The efficacy of a novel ultrasound score-based system, the US-9 score (joints assessed with US-7 plus knees), was also compared with the standard US-7 score. Methods: All the RA patients referred to the outpatient rheumatology clinic of Ghaem Hospital, Mashhad, Iran, during 2019-2020 were included. 28 joints were clinically examined to calculate DAS28. Nine joints were assessed comprising the German US-7 plus knees using grayscale ultrasonography (GSUS) and power Doppler ultrasonography (PDUS). Retrieved data were analyzed by SPSS software, version 22. The Spearman Correlation test was used to find the correlation between DAS28 and ultrasonographic findings. The statistical significance level was set at P<0.05. Results: This study was composed of thirty-five RA patients with a mean age of 49.1±12.0 years. US-7 synovitis scores in GSUS and PDUS were significantly correlated with DAS28 (P=0.02, r=0.38 and P=0.003, r=0.48, respectively). US-9 synovitis scores in GSUS and PDUS were also significantly correlated with DAS28 (P=0.003, r=0.49 and P=0.006, r=0.45, respectively). The synovitis score measured by GSUS was significantly correlated with the GSUS knee synovial score (P=0.01, r=0.42). Conclusion: Ultrasound assessment of large joints such as knees can be an effective approach to determining RA severity. However, it can be proposed that adding more involved joints into the sonographic assessment does not necessarily provide a better clinical correlation.

Haemophilic arthropathy: Diagnosis, management, and aging patient considerations.

Gene therapy and universal use of safer, more effective, and personalised prophylactic regimens (factor, and nonfactor) are expected to prevent joint bleeding and promote joint health in persons with haemophilia (PwH). Growing evidence suggests that subclinical bleeding, with active and inactive synovial proliferation, continues and haemophilic arthropathy remains a major morbidity in PwH despite early institution of joint prophylaxis. Joint health assessment is evolving with physical examination scores complementing imaging scores. Point-of-care ultrasound is emerging as a safe, cost-effective, and readily available tool for acute determination of musculoskeletal abnormalities, serial evaluation of joints for sonographic markers of haemophilic arthropathy, and in providing objective insight into the efficacy of new therapies. In acute haemarthrosis, arthrocentesis expedites recovery and prevent the vicious cycle of bleed-synovitis-rebleed. When synovial proliferation develops, a multidisciplinary team approach is critical with haematology, orthopaedics, and physiotherapy involvement. Synovectomy is considered for patients with chronic synovitis that fail conservative management. Non-surgical and minimally invasive procedures should always be offered and considered first. Careful patient selection, screening and early intervention increase the success of these interventions in reducing bleeding, pain, and improving joint function and quality of life. Chemical synovectomy is practical in developing countries, but radioactive synovectomy appears to be more effective. When surgical synovectomy is considered, arthroscopic/minimally invasive approach should be attempted first. In advanced haemophilic arthropathy, joint replacement and arthrodesis can be considered. While excited about the future of haemophilia management, navigating musculoskeletal challenges in the aging haemophilia population is equally important.

Work-related physical strain and development of joint inflammation in the trajectory of emerging inflammatory and rheumatoid arthritis: a prospective cohort study.

OBJECTIVES: Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently understood. We hypothesised that mechanical stress/physical strain is a risk factor for joint inflammation in RA. Therefore, we studied work-related physical strain in subjects with clinically suspected arthralgia (CSA) as a risk factor for the presence of imaging-detected subclinical joint inflammation and the development of clinical arthritis/RA. METHODS: In 501 CSA patients and 155 symptom-free persons' occupation-related physical strain was quantified using the International Standard Classification of Occupations. Contrast-enhanced hand-MRIs were made and evaluated for joint inflammation (sum of synovitis/tenosynovitis/osteitis). CSA patients were followed on RA development. Age relationship was studied using an interaction term of physical strain with age. RESULTS: The degree of physical strain in CSA is associated with the severity of joint inflammation, independent of educational-level/BMI/smoking (interaction physical strain-age p=0.007; indicating a stronger association with increasing age). Physical strain is associated with higher tenosynovitis scores, in particular. In symptom-free persons, physical strain was not associated with imaging-detected joint inflammation. Higher degrees of physical strain also associated with higher risks for RA development in an age-dependent manner (HR=1.20 (1.06-1.37)/10-year increase in age), independent of educational-level/BMI/smoking. This association was partly mediated by an effect via subclinical joint inflammation. CONCLUSIONS: Work-related physical strain increases the risk of subclinical joint inflammation and of developing RA. The age relationship suggests an effect of long-term stress or that tenosynovium is more sensitive to stress at older age. Together, the data indicate that mechanical stress contributes to the development of arthritis in RA.

Deconvolution of synovial myeloid cell subsets across pathotypes and role of COL3A1+ macrophages in rheumatoid arthritis remission.

Background: Monocyte/macrophage (Mo/Mp) is a critical cell population involved in immune modulation of rheumatoid synovitis (RA) across different pathotypes. This study aims to investigate the contribution of Mo/Mp clusters to RA activity, and the biological function of particular subtypes in RA remission. Methods: We integrated single-cell RNA sequencing datasets from 4 published and 1 in-house studies using Liger selected by comparison. We estimated the abundance of Mo/Mp subtypes in bulk RNA-seq data from the 81 patients of the Pathobiology of Early Arthritis Cohort (PEAC) using deconvolution analysis. Correlations between Mo/Mp subtypes and RA clinical metrics were assessed. A particular cell type was identified using multicolor immunofluorescence and flow cytometry in vivo and successfully induced from a cell line in vitro. Potential immune modulation function of it was performed using immunohistochemical staining, adhesion assay, and RT-qPCR. Results: We identified 8 Mo/Mp clusters. As a particular subtype among them, COL3A1+ Mp (CD68+, COL3A1+, ACTA2-) enriched in myeloid pathotype and negatively correlated with RA severity metrics in all pathotypes. Flow cytometry and multicolor immunofluorescence evidenced the enrichment and M2-like phenotype of COL3A1+ Mp in the myeloid pathotype. Further assays suggested that COL3A1+ Mp potentially attenuates RA severity via expressing anti-inflammatory cytokines, enhancing Mp adhesion, and forming a physical barrier at the synovial lining. Conclusion: This study reported unexplored associations between different pathologies and myeloid cell subtypes. We also identified a fibroblast-and-M2-like cluster named COL3A1+ Mp, which potentially contributes to synovial immune homeostasis. Targeting the development of COL3A1+ Mp may hold promise for inducing RA remission.

Associations between hyperuricemia and ultrasound-detected knee synovial abnormalities in middle-aged and older population: a cross-sectional study.

OBJECTIVES: Knee synovial abnormalities, potentially treatment targets for knee pain and osteoarthritis, are common in middle-aged and older population, but its etiology remains unclear. We examined the associations between hyperuricemia and knee synovial abnormalities detected by ultrasound in a general population sample. METHODS: Participants aged ≥ 50 years were from a community-based observational study. Hyperuricemia was defined as serum urate (SU) level > 416 µmol/L in men and > 357 µmol/L in women. Ultrasound of both knees was performed to determine the presence of synovial abnormalities, i.e., synovial hypertrophy, effusion, or Power Doppler signal (PDS). We examined the relation of hyperuricemia to prevalence of knee synovial abnormalities and its laterality, and the dose-response relationships between SU levels and the prevalence of knee synovial abnormalities. RESULTS: In total, 3,405 participants were included in the analysis. Hyperuricemia was associated with higher prevalence of knee synovial abnormality (adjusted odds ratio [aOR] = 1.21, 95% confidence interval [CI]: 1.02 to 1.43), synovial hypertrophy (aOR = 1.33, 95% CI: 1.05 to 1.68), and effusion (aOR = 1.21, 95% CI: 1.02 to 1.44), respectively. There were dose-response relationships between SU levels and synovial abnormalities. Additionally, the hyperuricemia was more associated with prevalence of bilateral than with that of unilateral knee synovial abnormality, synovial hypertrophy, or effusion; however, no significant association was observed between hyperuricemia and PDS. CONCLUSION: In this population-based study we found that hyperuricemia was associated with higher prevalence of knee synovial abnormality, synovial hypertrophy and effusion, suggesting that hyperuricemia may play a role in pathogenesis of knee synovial abnormalities.

The relationship of ALPK1, hyaluronic acid and M1 macrophage polarization in the temporomandibular joint synovitis.

M1 macrophage polarization and synovitis play an important role in the pathogenesis of temporomandibular joint osteoarthritis (TMJOA). Reduced molecular weight of hyaluronic acid (HA) in synovial fluid of patients with TMJOA. In addition, high molecular weight hyaluronic acid (HMW-HA) is often used clinically to treat TMJ inflammation. As a pattern recognition receptor of the cytoplasm, ALPK1 was found to be pro-inflammatory in a variety of diseases. However, the relationship of ALPK1, HA and M1 macrophage polarization in TMJ synovitis remains unclear. We aimed to investigate the role of ALPK1 and HA in macrophage polarization and TMJ synovitis and the underlying mechanisms. The results demonstrated that ALPK1 was highly upregulated in the synovial macrophages in the inflamed TMJ synovium of patients. Low molecular weight hyaluronic acid (LMW-HA) promoted the expression of ALPK1 and M1 macrophage-associated genes. Besides, rhALPK1 promoted the expression of M1 macrophage-associated factors and the nuclear translocation of PKM2. Furthermore, ALPK1 knockout mice exhibited limited infiltration of macrophages and decreased expression levels of M1 macrophage-associated genes in CFA-induced TMJ synovitis. While HMW-HA inhibited the expression of ALPK1 and M1 macrophage polarization. Our results elucidated that ALPK1 promoted TMJ synovitis by promoting nuclear PKM2-mediated M1 macrophage polarization, whereas HMW-HA inhibited the expression of ALPK1 as well as M1 macrophage polarization.

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review.

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.

Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.