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Autoimmunity underlies many painful disorders, such as enthesopathies, which localize to the enthesis. From infiltration of the synovium and axial skeleton by B cells, to disturbances in the ratio of M1/M2 enthesis macrophages, to CD8 + T cell mediated inflammation, autoimmune dysregulation is becoming increasingly well characterized in enthesopathies. Tissue resident B cells, macrophages, neutrophils, and T cells have also been localized in healthy human entheses. However, the potential developmental origins, presence, and role of immune cells (ICs) in enthesis development is not known. Here, we use single-cell RNA-sequencing analysis to describe IC subtypes present in the enthesis before, during, and after mineralization, and to infer regulatory interactions between ICs and mesenchymal cells (MCs). We report the presence of nine phenotypically distinct IC subtypes, including B cells, macrophages, neutrophils, and T cells. We find that specific IC subtypes may promote MC-proliferation and differentiation, and that MCs may regulate IC phenotype and autoimmunity. Our findings suggest that bidirectional regulatory interactions between ICs and MCs may be important to enthesis mineralization, and suggest that progenitor MCs have a unique ability to limit autoimmunity during development. [ABSTRACT FROM AUTHOR]

Background: Injuries to the glenoid labrum have been recognized as a source of joint pain and discomfort, which may be associated with the inflammatory responses that lead to the deterioration of labral tissue. However, it is unclear whether the torn labrum prompts mast cell (MC) activation, resulting in synovial inflammatory responses that lead to labral tissue degeneration. Purpose: To determine the potential influence of activated MC on synovial inflammatory responses and subsequent labral tissue degeneration and shoulder function deterioration in a rat model by monitoring MC behavior and sequential inflammatory responses within the synovial tissue and labral tissue after injury, suture repair, and MC stabilizer administration. Study Design: Controlled laboratory study. Methods: Anteroinferior glenoid labral tears were generated in the right shoulder of rats (n = 20) and repaired using a tunneled suture technique. Synovial tissue inflammatory responses were modulated in some rats with intraperitoneal administration of an MC stabilizer—cromolyn (n = 10). At weeks 1 and 3, MC activation, synovial inflammatory responses, and labral degeneration were histologically evaluated. Simultaneously, gait analysis was performed before and after surgical repair to assess the worsening of the shoulder function after the injury and treatment. Results: Resident MC degranulation after labral injury (50.48% ± 8.23% activated at week 1) contributed to the initiation of synovial tissue inflammatory cell recruitment, inflammatory product release, matrix metalloproteinase-13, and subsequent labral tissue extracellular matrix degeneration. The administration of cromolyn, an MC stabilizer, was found to significantly diminish injury-mediated inflammatory responses (inflammatory cell infiltration and subsequent proinflammatory product secretion) and improve shoulder functional recovery. Conclusion: MC activation is responsible for labral tear–associated synovial inflammation and labral degeneration. The administration of cromolyn can significantly diminish the cascade of inflammatory reactions after labral injury. Clinical Relevance: Our findings support the concept that MC stabilizers may be used as a complementary therapeutic option in the treatment and repair of labral tears. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To clarify the anti-inflammatory effect of platelet lysate (PL) on equine persistent synovitis by using a model of synovitis induced by monoiodoacetic acid (MIA). METHODS: Nonseptic synovitis was induced by administering MIA into both antebrachiocarpal joints of 6 clinically healthy horses on day 0. On days 23, 30, and 37, carpal circumference measurement and synovial fluid collection for assays (leucocytes, LDH, tumor necrosis factor-a, and TGF-ß1) were performed, after which PL was injected into 1 antebrachiocarpal joint and saline into the contralateral joint. Synovium and synovial fluid were obtained on day 44 for histological analysis and quantification of inflammation-related genes (matrix metalloproteinase-13, a disintegrin and metalloproteinase with thrombospondin motifs 4, receptor activator of nuclear factor β ligand, and collagen type I a2 chain) and the abovementioned proteins. RESULTS: The LDH level on day 44 was significantly lower in the PL-injected joint than in the saline-treated one. However, no significant differences were found in the other indices quantified, including osteoclast counts on the synovium. CONCLUSIONS: Multiple IA administration of PL does not exert anti-inflammatory effects on the equine persistent synovitis induced by MIA. CLINICAL RELEVANCE: Intra-articular PL administration did not alter many inflammatory biomarkers, suggesting that PL does not have a direct anti-inflammatory effect. However, the reduction in synovial LDH levels suggests that PL promoted joint tissue repair and may consequently alleviate inflammation at the site of administration. [ABSTRACT FROM AUTHOR]

Aim: This study aims to assess the effectiveness of therapy of human synovial membrane-derived MSCs (SM-MSC) from OA grade IV patients in treating knee OA. Methods: SM-MSC were isolated from patients undergoing total knee replacement surgery, cultured to the fourth passage, and characterized using flow cytometry. Differentiation potential was assessed through lineage-specific staining. Osteoarthritis was induced in 24 Wistar rats via monosodium iodoacetate (MIA). The rats were divided into three groups: negative control, OA control, and OA treated with SM-MSC. Radiological, histopathological, and molecular analyses were conducted to evaluate cartilage repair and gene expression. Results: Flow cytometry confirmed the MSC phenotype of SM-MSC, and successful differentiation was observed. Radiological and histopathological analyses showed significant improvement in the SM-MSC treated group, with reduced cartilage damage and higher Safranin O staining compared to the OA control group. Gene expression analysis indicated increased type-2 collagen (COL-2) expression in the SM-MSC treated group, although MMP-13 levels remained unchanged across all groups. Conclusion: Human SM-MSCs from OA grade IV patients significantly improved cartilage repair in an OA rat model, demonstrating their potential as a therapeutic option for OA. To enhance long-term efficacy and anti-inflammatory effects, further studies are needed to optimize treatment protocols, including injection frequency and dosage. [ABSTRACT FROM AUTHOR]

Objective: Synovial fluid (SF)–derived T cells are frequently studied as a proxy for investigating the synovial tissue (ST) T cell infiltrate in inflammatory arthritis. However, because ST is the primary site of inflammatory activity, there is debate as to whether SF provides a true reflection of the ST T cell population. Methods: In this study, we used single‐cell RNA sequencing paired with single‐cell T cell receptor (TCR) sequencing to directly compare memory T cells from paired samples of SF and ST from six patients with inflammatory arthritis to investigate their similarity in terms of TCR repertoire and T cell subset composition. Results: The TCR repertoires of SF and ST T cells were strikingly similar, particularly for CD8+ T cells. A median of 49% of the total CD8+ TCR repertoire in SF was shared with ST, compared with 20% shared with blood. Similarly, 47% of the ST CD8+ TCR repertoire was shared with SF compared to 25% with blood. Furthermore, once the effect of collagenase digestion on gene expression by ST T cells had been accounted for, the frequencies of specific CD8+ and CD4+ T cell subsets were, in general, similar in SF and ST and were distinct from blood. Conclusion: Our results suggest that T cells migrate and equilibrate between the SF and ST and maintain similar phenotypes in both sites. We conclude that SF is an appropriate proxy for investigating the T cell infiltrate in inflamed synovium, particularly in terms of investigating the TCR repertoire. [ABSTRACT FROM AUTHOR]

Objective: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft‐tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. Methods: The expression of synovial genes from 6 control individuals, 7 patients with osteoarthritis (OA), and 19 patients with PVNS was analyzed via RNA sequencing. Protein profiles from 5 control individuals, 10 patients with OA, and 32 patients with PVNS were analyzed using label‐free proteomics. Microarray and reverse transcription–polymerase chain reaction analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from tissue of patients with PVNS. Various signaling pathway inhibitors, small interfering RNAs, and Western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. Results: In total, 522 differentially expressed proteins were identified in the tissues of patients with PVNS. By integrating RNA sequencing and microarray analyses, significant changes in the expression of epithelial–mesenchymal transition (EMT)‐related genes, including transforming growth factor TGF‐b induced, neural cadherin, epithelial cadherin, SNAIL, and TWIST, were confirmed in the tissue of patients with PVNS compared to the control tissue. In vitro, TGFβ induced EMT and increased epithelial cell migration and invasion. Moreover, TGFβ not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. Conclusion: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGFβ in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy. [ABSTRACT FROM AUTHOR]

Objectives: Detection of synovitis is essential for assessing the activity and predicting the prognosis of rheumatoid arthritis (RA). The aim of this study was to investigate the diagnostic performance of superb microvascular imaging (SMI) in RA patients with high, moderate, and low activity. Methods: One hundred four patients with active RA were selected from the hospital between May 2022 and August 2023. The study observed the correlation between bone erosion of the carpal joint, joint cavity effusion, thickness of synovial hyperplasia of the carpal joint, positivity rate of synovial blood vessels, and their semiquantitative scores with the clinical disease activity of RA using SMI examination. Results: The detection of synovial hyperplasia thickness and joint effusion in the high-activity group was higher than that in the low-activity group, and the difference was statistically significant (P < 0.05). The quantitative SMI test demonstrated that the synovial blood flow grading and semiquantitative grade increased gradually with activity level (P<0.05). During the high, moderate, and low-activity groups, the vascular index (VI) value of the hyperplastic synovial membrane decreased gradually, showing statistical significance both between and within the groups (P<0.05). Conclusion: SMI technology exhibited high sensitivity and accuracy in assessing disease activity in RA. It holds significant clinical application value as a reliable auxiliary tool for assessing disease activity in RA and treatment. Key Points • Super micro-vascular imaging (SMI) demonstrated higher detection rates of microvessels in RA patients with high disease activity compared to those with low activity, showing statistical significance. • The quantitative SMI test revealed a clear correlation between synovial blood flow grading and disease activity levels in RA patients, highlighting the potential of SMI as a valuable tool for disease activity and treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Background: The giant cell tumor of the tendon pod is a benign neoplasia that can be present in any bone or tendon pod. Its etiology is unknown. Nevertheless, it is related to a chronic inflammatory process. It usually occurs in women between the third and fifth decade as a palpable and painless mass and slow growth, although it can be deformed and lead to limb loss. Case presentation: In this report, we present the case of an 11-year-old male patient, which began on June 21, 2020, with a blunt trauma. An ultrasound was performed, reporting compatible data with synovial sarcoma. Magnetic resonance was requested, with mass evidence in soft tissues in central and planting portions. A surgical procedure with a split and biopsy of the mass was carried out. The specimen was sent to the Pathology Department, leading to a diagnosis of a giant cell tumor of the tendon pod. Conclusions: The giant cell tumor of the tendon pod is rare. However, in some cases, it is crucial to consider it as a differential diagnosis. The surgical management of this entity has proven to reduce recurrence rates. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a prevalent clinical condition affecting the entire joint, characterized by its multifactorial etiology and complex pathophysiology. The onset of OA is linked to inflammatory mediators produced by the synovium, cartilage, and subchondral bone, all of which are closely tied to cartilage degradation. Consequently, OA may also be viewed as a systemic inflammatory disorder. Emerging studies have underscored the significance of T cells in the development of OA. Notably, imbalances in Th1/Th2 and Th17/Treg immune cells may play a crucial role in the pathogenesis of OA. This review aims to compile recent advancements in understanding the role of T cells and their Th/Treg subsets in OA, examines the immune alterations and contributions of Th/Treg cells to OA progression, and proposes novel directions for future research, including potential therapeutic strategies for OA. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests that synovial inflammation plays a pivotal role in knee osteoarthritis. Although biomechanical findings have shown that medial open-wedge proximal tibial osteotomy (OWPTO) decreases medial compartment loading by correcting knee alignment, the relationship between knee alignment and synovial inflammation in the biological microenvironment has not yet been elucidated. Purposes: To investigate the relationship between preoperative and postoperative knee alignment and synovial gene expression and to determine the cutoff point of postoperative knee alignment at which gene expression of synovial inflammation improves. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 36 patients with osteoarthritis who underwent OWPTO between June 2018 and May 2020 were enrolled. Synovial tissue was collected from affected knees during initial OWPTO and plate removal surgeries, and gene expression associated with the pathogenesis of osteoarthritis in the synovial tissue was investigated using real-time polymerase chain reaction. The correlation between weightbearing line ratio (WBLR) and synovial gene expression was determined. Receiver operating characteristic curve analysis was used to determine the cutoff values of WBLR for improving gene expression. The participants were divided into 2 groups, according to the cutoff values of their WBLR, and compared according to Knee injury and Osteoarthritis Outcome Score (KOOS) and synovial gene expression. Results: Postoperative WBLR was correlated with gene expression of interleukin 1β (IL1B) (ρ = −0.43; P =.008) and of interleukin 6 (IL6) (ρ = −0.41; P =.01). The cutoff value to predict improvement of IL6 was postoperative WBLR of 52%, with an area under the curve of 0.74 (P =.03). Patients with WBLR of <52% showed higher postoperative inflammatory gene (IL1B [ P =.04] and IL6 [ P =.03]) and inferior postoperative KOOS values compared with those with WBLR of >52%. Conclusion: The novel cutoff alignment for biological improvement after OWPTO in patients with medial compartment osteoarthritis was determined to be WBLR of 52%, and WBLR of <52% was associated with higher residual intra-articular inflammation and poor clinical outcomes. After accounting for surgical errors, the surgeon should set the target surgical alignment so that the postoperative WBLR does not fall below 52%. [ABSTRACT FROM AUTHOR]

Cationic contrast‐enhanced computed tomography (CECT) capitalizes on increased contrast agent affinity to the charged proteoglycans in articular cartilage matrix to provide quantitative assessment of proteoglycan content with enhanced images. While high resolution microCT has demonstrated success, we investigate cationic CECT use in longitudinal in vivo imaging at clinical resolution. We hypothesize that repeated administration of CA4+ will have no adverse side effects or complications, and that sequential in vivo imaging assessments will distinguish articular cartilage repair tissue from early degenerative and healthy cartilage in critically sized chondral defects. In an established equine translational preclinical model, lameness and synovial effusion scores are similar to controls after repeated injections of CA4+ (eight injections over 16 weeks) compared to controls. Synovial fluid total protein, leukocyte concentration, and sGAG and PGE2 concentrations and articular cartilage and synovial membrane scores are also equivalent to controls. Longitudinal in vivo cationic CECT attenuation in repair tissue is significantly lower than peripheral to (adjacent) and distantly from defects (remote sites) by 4 weeks (p < 0.001), and this difference persists until 16 weeks. At the 6‐ and 8‐week time points, the adjacent locations exhibit significantly lower cationic CECT attenuation compared with the remote sites, reflecting peri‐defect degeneration (p < 0.01). Cationic CECT attenuation at clinical resolution significantly correlates with cationic CECT (microCT) (r = 0.69, p < 0.0001), sGAG (r = 0.48, p < 0.0001), and ICRS II histology score (r = 0.63, p < 0.0001). In vivo cationic CECT imaging at clinical resolution distinguishes fibrous repair tissue from degenerative and healthy hyaline cartilage and correlates with molecular tissue properties of articular cartilage. [ABSTRACT FROM AUTHOR]

Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast‐like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared with normal synovial tissues (ST). Power Doppler ultrasound‐guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA ST. Toll‐like receptors and tumor necrosis factor (TNF) are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and transactivate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti‐TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease‐modifying antirheumatic drugs reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, interleukin‐6 receptor (IL‐6R) antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF‐κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function. [ABSTRACT FROM AUTHOR]

The enthesitis hypothesis posits that enthesitis is a primary lesion and that inflammation at the enthesis initiates the musculoskeletal symptoms of psoriatic arthritis (PsA) and spondyloarthropathies (SpA). The hypothesis suggested that inflamed entheseal tissue near the synovium could trigger cytokine-mediated synovitis, that enthesis bone anchorage could explain osteitis, and that the location of entheses at the soft tissue interface could explain dactylitis. Advances in imaging techniques that allow better visualization of enthesitis lesions and the development of animal models have allowed evolution of the concept of enthesitis as a central mechanistic driver of musculoskeletal symptoms in PsA and SpA. A debate between Drs. Dennis McGonagle and Bruce Kirkham at the Group for Research on Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting discussed the data supporting and refuting this hypothesis in PsA and SpA, respectively. The major points of this debate are summarized in this article. [ABSTRACT FROM AUTHOR]

Objective: HLA‐DR–expressing fibroblast‐like synoviocytes (FLS) are a prominent cell type in synovial tissue in chronic inflammatory forms of arthritis. FLS‐derived extracellular matrix (ECM) proteins, including fibronectin‐1 (FN1), contain immunogenic CD4+ T cell epitopes in patients with postinfectious Lyme arthritis (LA). However, the role of FLS in presentation of these T cell epitopes remains uncertain. Methods: Primary LA FLS and primary murine FLS stimulated with interferon gamma (IFNγ), Borrelia burgdorferi, and/or B burgdorferi peptidoglycan (PG) were assessed for properties associated with antigen presentation. HLA‐DR–presented peptides from stimulated LA FLS were identified by immunopeptidomics analysis. OT‐II T cells were co‐cultured with stimulated murine FLS in the presence of cognate ovalbumin antigen to determine the potential of FLS to act as inducible antigen presenting cells (APCs). Results: FLS expressed HLA‐DR molecules within inflamed synovial tissue and tendons from patients with postinfectious LA in situ. Major histocompatibility complex (MHC) class II and co‐stimulatory molecules were expressed by FLS following in vitro stimulation with IFNγ and B burgdorferi and presented both foreign and self‐MHC‐II peptides, including an immunogenic T cell epitope derived from Lyme autoantigen FN1. Stimulated FLS induced proliferation of naive OT‐II CD4+ T cells that were dependent on OT‐II antigen and CD40. Stimulation with B burgdorferi PG enhanced FLS‐mediated T cell activation. Conclusion: MHC‐II+ FLS are inducible APCs that can induce CD4+ T cell activation in an antigen‐ and CD40‐dependent manner. Activated FLS can also present ECM‐derived Lyme autoantigens, implicating FLS in amplifying tissue‐localized autoimmunity in LA. [ABSTRACT FROM AUTHOR]

Background and Objectives: Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive, benign neoplasm arising from the synovium of joints, tendon sheaths, and bursa. There are two main subtypes of TGCT: localized-type TGCT(L-TGCT) and diffuse-type TGCT (D-TGCT). While surgical excision is still considered the gold standard of treatment, the high recurrence rate, especially for D-TGCT, may suggest the need for other treatment modalities. Materials and Methods: This study reviews current literature on the current treatment modalities for refractory-relapsed TGCT disease. Results: The gold standard of treatment modality in TGCT remains surgical excision of the tumor nevertheless, the elevated recurrence rate and refractory disease, particularly in D-TGCT indicates and underscores the necessity for additional treatment alternatives. Conclusions: TGCT is a benign tumor with inflammatory features and a potential destructive and aggressive course that can lead to significant morbidity and functional impairment with a high impact on quality of life. Surgical resection remains the gold standard current treatment and the optimal surgical approach depends on the location and extent of the tumor. Systemic therapies have been recently used for relapsed mainly cases. [ABSTRACT FROM AUTHOR]

Hemophilia, which is a rare disease, results from congenital deficiencies of coagulation factors VIII and IX, respectively, leading to spontaneous bleeding into joints, resulting in hemophilic arthropathy (HA). HA involves complex processes, including synovial proliferation, angiogenesis, and tissue remodeling. Despite ongoing research, factors contributing to HA progression, especially in adults with severe HA experiencing joint pain, remain unclear. Blood markers, particularly collagen-related ones, have been explored to assess joint health in hemophilia. For example, markers like CTX-I and CTX-II reflect bone and cartilage turnover, respectively. Studies indicate elevated levels of certain markers post-bleeding episodes, suggesting joint health changes. However, longitudinal studies on collagen turnover and basement membrane or endothelial cell markers in relation to joint outcomes, particularly during painful episodes, are scarce. Given the role of the CX3CL1/CX3XR1 axis in arthritis, other studies investigate its involvement in HA. The importance of different inflammatory and bone damage biomarkers should be assessed, alongside articular cartilage and synovial membrane morphology, aiming to enhance understanding of hemophilic arthropathy progression. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) can lead to chronic joint pain, and currently there are no methods available for complete cure. Utilizing the Gene Expression Omnibus (GEO) database for bioinformatics analysis combined with Mendelian randomization (MR) has been widely employed for drug repurposing and discovery of novel therapeutic targets. Therefore, our research focus is to identify new diagnostic markers and improved drug target sites. Methods: Gene expression data from different tissues of synovial membrane, cartilage and subchondral bone were collected through GEO data to screen out differential genes. Two-sample MR Analysis was used to estimate the causal effect of expression quantitative trait loci (eQTL) on OA. Through the intersection of the two, core genes were obtained, which were further screened by bioinformatics analysis for in vitro and in vivo molecular experimental verification. Finally, drug prediction and molecular docking further verified the medicinal value of drug targets. Results: In the joint analysis utilizing the GEO database and MR approach, five genes exhibited significance across both analytical methods. These genes were subjected to bioinformatics analysis, revealing their close association with immunological functions. Further refinement identified two core genes (ARL4C and GAPDH), whose expression levels were found to decrease in OA pathology and exhibited a protective effect in the MR analysis, thus demonstrating consistent trends. Support from in vitro and in vivo molecular experiments was also obtained, while molecular docking revealed favorable interactions between the drugs and proteins, in line with existing structural data. Conclusion: This study identified potential diagnostic biomarkers and drug targets for OA through the utilization of the GEO database and MR analysis. The findings suggest that the ARL4C and GAPDH genes may serve as therapeutic targets, offering promise for personalized treatment of OA. [ABSTRACT FROM AUTHOR]

Objectives To introduce and evaluate a simple method for assessing joint inflammation and structural damage on whole-body MRI (WBMRI) in juvenile idiopathic arthritis (JIA), which is usable in clinical practice. Methods The proposed system utilizes post-contrast Dixon WBMRI scans. Joints are assessed for synovitis (grade 0–2) and structural damage (present/absent) at 81 sites. The synovitis grading is based on features including above-normal intensity synovial enhancement, synovial hypertrophy, joint effusion, subarticular bone marrow oedema and peri-articular soft tissue oedema. This system was evaluated in a prospective study of 60 young people (47 patients with JIA and 13 controls with non-inflammatory musculoskeletal pain) who underwent a WBMRI. Three readers (blinded to diagnosis) independently reviewed all images and re-reviewed 20 individual scans. The intra- and inter-reader overall agreement (OA) and the intra- and inter-reader Gwet's agreement coefficients 2 (GAC2) were measured for the detection of a) participants with ≥1 joint with inflammation or structural damage and b) joint inflammation or structural damage for each joint. Results The inter-reader OA for detecting patients with ≥1 joint with inflammation, defined as grade 2 synovitis (G2), and ≥1 joint with structural damage were 80% and 73%, respectively. The intra-reader OA for readers 1–3 was 80–90% and 75–90%, respectively. The inter-reader OA and GAC2 for joint inflammation (G2) at each joint were both ≥85% for all joints but were lower if grade 1 synovitis was included as positive. Conclusion The intra- and inter-reader agreements of this WBMRI assessment system are adequate for assessing objective joint inflammation and damage in JIA. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic osteoarthritis (PTOA) arises secondarily to joint trauma and is driven by catabolic inflammatory pathways. Alpha-2-macroglobulin (α2M) is a naturally occurring proteinase inhibitor found in human serum and synovial fluid that binds proteases as well as proinflammatory cytokines involved in the pathogenesis of PTOA. Purpose: (1) To investigate the therapeutic potential of intra-articular α2M injections during the acute stages of PTOA by inhibiting inflammatory pathways driven by the cytokines expressed by the synovium in a large preclinical Yucatan minipig model and (2) to determine if 3 intra-articular α2M injections have greater chondroprotective effects compared with 1 intra-articular injection. Study Design: Controlled laboratory study. Methods: A total of 48 Yucatan minipigs were randomized into 4 groups (n = 12 each): (1) modified intra-articular drilling (mIAD) and saline (mIAD + saline), (2) mIAD and 1 intra-articular α2M injection (mIAD +α2M-1), (3) mIAD and 3 α2M injections (mIAD +α2M-3), and (4) sham control. Surgical hindlimbs were harvested at 15 weeks after surgery. Cartilage degeneration, synovial changes, inflammatory gene expression, and matrix metalloproteinase levels were evaluated. Gait asymmetry was measured before and after surgery using a pressure-sensing walkway system. Results: Macroscopic lesion areas and microscopic cartilage degeneration scores were lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05) and similar to those in the sham group (P >.05). Synovial membrane scores of the mIAD +α2M-1 and mIAD +α2M-3 groups were lower than that of the mIAD + saline group (P <.05) and higher than that of the sham group (P <.05). Interleukin-1 beta, nuclear factor kappa B, and tumor necrosis factor alpha mRNA expression in the synovium and matrix metalloproteinase-1 levels in synovial fluid were significantly lower in the mIAD +α2M-1 and mIAD +α2M-3 groups compared with the mIAD + saline group (P <.05). No significant differences were observed between the mIAD +α2M-1 and mIAD +α2M-3 groups for all measured outcomes. There were early changes in gait (P <.05) between preoperative and postoperative time points for the mIAD + saline, mIAD +α2M-1, and mIAD +α2M-3 groups that normalized by 15 weeks. Conclusion: Animals receiving early α2M treatment exhibited less cartilage damage, milder synovitis, and lower inflammation compared with animals with no α2M treatment. These results exemplify the early anti-inflammatory effects of α2M and provide evidence that intra-articular α2M injections may slow the progression of PTOA. Clinical Relevance: In patients presenting with an acute joint injury, an early intervention with α2M may have the potential to reduce cartilage degeneration from catabolic pathways and delay the development of PTOA. [ABSTRACT FROM AUTHOR]

Objective: Rheumatoid arthritis causes inflammation, pain, and joint degradation, necessitating treatment with anti-inflammatory drugs and corticosteroids, posing various challenges. We aimed to evaluate the effects of photobiomodulation (PBM) at two different doses associated to platelet-rich plasma (PRP) in an in vivo model of induced acute arthritis in Wistar rats' knee. Methods: Eighty-four Wistar rats were assigned into seven groups, including animals treated with PBM and/or PRP. On day 0, arthritis was induced in sham and treated groups through the intra-articular injection of zymosan (200μg). Twenty-four hours after induction, the PBM groups were treated with an AsGaAl laser, whereas the PRP-treated groups received intra-articular injections with a concentration of 8 · 105 platelets obtained from another four animals. After 3 days, the animals were euthanized, and the interleukin (IL)-6 and complement C3 gene and protein expression levels were analyzed. Statistical analysis was performed using the mean - SD with analysis of variance and Tukey's posttest, with a significance level set at 5% (p < 0.05). Results: Synovial inflammation decreased in PBM-treated groups; however, PRP alone showed no significant difference. Gene expression analysis revealed a significant difference in IL-6 and C3 levels in the PBM and PBM+PRP-treated groups. Meanwhile, the PRP alone group exhibited significance for IL-6. Moreover, the PBM and PBM+PRP-treated groups showed a significant difference in C3 protein expression levels, whereas the PRP alone group showed no difference. Conclusion: The increase in cellular activity in the synovial membrane and the decrease protein expression levels are owing to the reduction in proinflammatory mediators following PBM therapy. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) in horses often affects the metacarpal/metatarsophalangeal (MCP/MTP) joints and its detection in the early stages is crucial for effective management. I t was hypothesized that the extent of cartilage damage positively correlates with synovial membrane (SM) and synovial fluid (SF) pathological findings in the MCP/MTP joints of Serbian mountain horses that transported heavy loads but did not show signs of lameness. The study was conducted on 32 MCP/MTP joints of eight horses between seven to 12 years of age. Horse limbs were transferred from the abattoir to the necropsy room and SF was sampled. Its appearance, total nucleated cell count (TNCC), mononuclear cell count (MNC), total proteins (TP), and haptoglobin (Hp) were determined. Samples of SM were collected from the dorsal palmar/plantar pouch for histology. A macroscopic examination of gross condylar pathology of the third metacarpal/metatarsal bone was performed with Indian Ink staining. Scoring was done based on Osteoarthritis Research Society International recommendations. SF was clear, pale yellow, and mostly fairly viscous. Half of the samples had TNCC above, and all had TP within the reference range. Hp values were below the reference range and were omitted from further analyses. TNCC correlated with MNC (ρs=0.81, P<0.001), microscopic (ρs=0.62, P=0.003) and macroscopic scores (ρs=0.47, P=0.008). In addition, MNC correlated with macroscopic scores (ρs=0.40, P=0.03). All pathological findings were mild and their correlation indicated that these processes are interrelated and that could be ascribed to early OA. [ABSTRACT FROM AUTHOR]

Objective: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features. Methods: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206− classical and CD206+ nonclassical macrophages, and CD8+ and CD4+ T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies. Results: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1‐like macrophage–rich synovial lining was associated with greater lining hypertrophy and higher (CD45+) pan–immune cell and CD8+ T cell infiltration. Conclusion: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1‐like macrophage and CD8+ T cell infiltration, and thicker, M1‐like macrophage–rich synovial lining, and (2) those with an M2‐like macrophage transcriptomic signature, greater M2/M1‐like macrophage ratios, and thinner, M2‐like macrophage–rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity. [ABSTRACT FROM AUTHOR]

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetric polyarthritis. RA is routinely treated by various systemic drugs; on the other hand, administration of intra-articular corticosteroids or different types of synovectomies can be used in case of systemic medication's failure. Chemical, radio isotopic, and surgical synovectomies are being used as therapeutic options for chronic synovitis to improve joint function. Chemical synovectomy is not well tolerated, and the long-term response is relatively low. Surgical synovectomy has a better success rate, but it recommends higher expenses. In radiation synovectomy, radioactive labeled particles are applied directly in the articular cavity, followed by homogeneous distribution in joint. Next, the radioactive particles are transported in the depth of synovia and phagocytized by inflammatory cells. Finally, the radiation leads to fibrosis and sclerosis of formerly inflamed synovial membrane; thus, it stops the inflammation and reduces the symptoms. It has a success rate of 40–100% and its effect can be similar to surgical synovectomy. Materials and methods: Thirty-one patients with resistant monoarthritis of the knee were enrolled in this study. One millicurie of phosphorus-32 was injected into patients' knee via US guide. Saline was injected afterwards to prevent leakage. Direct pressure was performed after removing the needle and the knee was flexed slowly to ensure homogenous distribution and fixed with a splint for 1 to 2 weeks. Patients were followed up after 2 weeks, 1 month, 2 months, and 6 months. The following variables were assessed by the treating rheumatologist: patients' pain, joint tenderness, effusion, and ROM. At the time of injection and after the first week, patients were investigated for any complication including infection, necrosis, pain, and swelling. The effect of clinical characteristics and demographic data on existing complications and the changes of pain, joint tenderness, effusion, and ROM was assessed. Results: Thirty-one patients with the mean age of 54.5 ± 12.2 years and the mean disease duration of 12 ± 6.5 years were enrolled in this study. Mean DAS-28 ESR score for our patients was 4 ± 0.7. The pain, effusion, and reduced ROM were decreased significantly after all follow-up intervals. Knee tenderness was not affected in the first 2 weeks, but it was reduced significantly after 1, 2, and 6 months. No serious complications like infection and necrosis were reported through our study. 51.6% and 54.8% of our patients reported pain and swelling in the administration site. Furthermore, 19.4% and 16.1% of patients reported deterioration of pain and effusion in the first week of injection. Conclusion: In our study, we demonstrated that pain, tenderness, effusion, and ROM are improved after radiation synovectomy with phosphorus-32. We also showed that there was no serious adverse effect like infection and necrosis. However, more than half of our patients experienced pain and swelling of injection site at the time of administration. Key points • We demonstrated the efficacy of radiation synovectomy as a medication for monoarthritis. • The results of our study can lead to a bigger clinical trial to assess the benefits and adverse effects of radiation synovectomy in comparison to treatment with local or systemic corticosteroids. [ABSTRACT FROM AUTHOR]

Summary: With the rapid advancement of new energy sources, distributed power supplies have gained widespread adoption in DC microgrid systems. The stability of the DC‐DC converter, serving as the central component for energy transfer between the distributed power supply and the DC bus, holds significant importance in ensuring the overall system performance. Due to the intricate nature of real‐world operating conditions, the DC bus voltage is frequently subject to uncertainties such as fluctuations in distributed power supplies and random variations in loads. As a consequence, the reliability of DC‐DC converters faces escalating demands, making it challenging for conventional linear controllers to ensure consistent operation of DC‐DC converters across a broad range. This study focuses on addressing this issue by investigating the Cuk converter, which serves as a representative example of a single‐input multiple‐output system. The operating characteristics and control challenges of the Cuk converter are analyzed, and a nonlinear control strategy based on target holographic feedback is proposed to enhance the system's stability. Considering the non‐minimum phase characteristics of the Cuk converter and its inability to be linearized through exact feedback, a sliding mode variable structure control approach is introduced, utilizing target holographic feedback. Through simulation and experimental analysis, the effectiveness of the model and the theoretical analysis are validated. [ABSTRACT FROM AUTHOR]

Background: We report a rare case of posterior cruciate ligament (PCL) calcification, which has only been reported in two case studies on PubMed. Case presentation: A 71-year-old man developed left popliteal pain in the morning without any history of trauma and the pain became severe that night. On the following day, he presented to our department. The patient could not flex his left knee at all due to pain and swelling. CT and MRI scans showed calcification behind the PCL with mild osteoarthritic changes and accumulation of synovial fluid in the joint. Synovial fluid analysis did not reveal any crystals. Blood tests at first admission showed inflammation, hyperglycemia, and low blood uric acid levels. Although the patient's knee joint was injected with steroids, his symptoms did not improve. Thus, we performed arthroscopic surgery two days after symptoms had appeared. Intraoperatively, we observed a white, soft tissue in the synovial membrane behind the PCL. Part of this tissue was collected for histological analysis, which revealed sparse fibers with calcium deposits. Immediately after surgery, the patient's symptoms were completely gone. Afterward, the patient remained asymptomatic one month after surgery. Conclusion: This is the first reported case of debridement of PCL calcification and ossification that was performed soon after symptoms appeared. In addition, we demonstrated that early debridement led to complete recovery. [ABSTRACT FROM AUTHOR]

AIM: To investigate whether Miaoyao Tongfeng prescription (MTP) attenuates oxidative stress injury in gouty arthritis rats by regulating Kelch-like epicklorohydrin-related protein 1 (Keap1) /nuclear factor E2-related factor 2 (Nrf2) signaling pathway. METHODS: Fifty male Sprague-Dawley rats were randomly divided into control group, model group, MTP group, Nrf2 inhibitor all-trans retinoic acid (ATRA) group and MTP+ATRA group. The 3% potassium oxonate solution (10 mL/kg) was injected intraperitoneally twice a day for 1 week, and then 0. 2 mL sodium urate suspension (25 g/L) was injected into the right knee joints to establish the gouty arthritis model. All rats were sacrificed 48 h after modeling. Grades of swelling in the knee joints were evaluated, and HE staining was used to observe the pathological changes of knee joints. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA) and interleukin-1β (IL-1β) were detected using kits. The mRNA levels of Nrf2, Keap1, heme oxygenase-1 (HO-1), IL-1β, NAD (P) H: quinone oxidoreductase 1 (NQO1) in the synovial membrane of the knee joints were detected by qRT-PCR. Western blot was used to detect the expression of Nrf2, Keap1 and NQO1 in the synovial membrane of the knee joints. RESULTS: Compared with model group, MTP significantly reduced the degree of knee joint swelling, and attenuated the pathological injury of knee synovial membrane. It also inhibited the expression of MDA and IL-1β, but increased the expression of SOD. The mRNA expression of HO-1, and the mRNA and protein expression of Nrf2 and NQO1 in synovium were up-regulated, while the levels of IL-1β mRNA, Keap1 mRNA and Keap1 protein were down-regulated. CONCLUSION: Miaoyao Tongfeng prescription shows promise in the prevention and treatment of gouty arthritis through regulating Nrf2 and down⁃ stream anti-oxidation genes. [ABSTRACT FROM AUTHOR]

Objective: Subsets of CD21−/low memory B cells (MBCs), including double‐negative (DN, CD27−IgD−) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21−/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21−/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). Methods: Clinical observations were combined with flow cytometry (n = 36) and single‐cell RNA sequencing (scRNA‐seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA‐seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. Results: CD21−/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up‐regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin‐mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. Conclusion: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization. [ABSTRACT FROM AUTHOR]

Objective: Fibroblast‐like synoviocytes (FLS) contribute to the pathogenesis of rheumatoid arthritis (RA), in part due to activation of the proinflammatory transcription factor NF‐κB. Neddylation is modulated by the negative regulator of ubiquitin‐like protein (NUB) 1. We determined whether NUB1 and neddylation are aberrant in the models with RA FLS, thereby contributing to their aggressive phenotype. Methods: Models with RA or osteoarthritis (OA) FLS were obtained from arthroplasty synovia. Real‐time quantitative polymerase chain reaction and Western blot analysis assessed gene and protein expression, respectively. NUB1 was overexpressed using an expression vector. NF‐κB activation was assessed by stimulating FLS with interleukin (IL)‐1β. Neddylation inhibitor (MLN4924) and proteasome inhibitor were used in migration and gene expression assays. MLN4924 was used in the model with K/BxN serum‐transfer arthritis. Results: Enhanced H3K27ac and H3K27me3 peaks were observed in the NUB1 promoter in the OA FLS compared with the RA FLS. NUB1 was constitutively expressed by FLS, but induction by IL‐1β was significantly greater in the OA FLS. The ratio of neddylated cullin (CUL) 1 to nonneddylated CUL1 was lower in the OA FLS than the RA FLS. NUB1 overexpression decreased NF‐κB nuclear translocation and IL‐6 messenger RNA (mRNA) in IL‐1β–stimulated the RA FLS. MLN4924 decreased CUL1 neddylation, NF‐κB nuclear translocation, and IL‐6 mRNA in IL‐1β–stimulated the RA FLS. MLN4924 significantly decreased arthritis severity in the model with K/BxN serum‐transfer arthritis. Conclusion: CUL1 neddylation and NUB1 induction is dysregulated in the models with RA, which increases FLS activation. Inhibition of neddylation is an effective therapy in an animal model of arthritis. These data suggest that the neddylation system contributes to the pathogenesis of RA and that regulation of neddylation could be a novel therapeutic approach. [ABSTRACT FROM AUTHOR]

Background: Mesenchymal stem cells (MSCs) derived from the synovium, known as synovium mesenchymal stem cells (SMSCs), exhibit significant potential for articular cartilage regeneration owing to their capacity for chondrogenic differentiation. However, the microRNAs (miRNAs) governing this process and the associated mechanisms remain unclear. While mechanical stress positively influences chondrogenesis in MSCs, the miRNA‐mediated response of SMSCs to mechanical stimuli is not well understood. Objective: This study explores the miRNA‐driven mechano‐transduction in SMSCs chondrogenesis under mechanical stress. Methods: The surface phenotype of SMSCs was analysed by flow cytometry. Chondrogenesis capacities of SMSCs were examined by Alcian blue staining. High throughput sequencing was used to screen mechano‐sensitive miRNAs of SMSCs. The RNA expression level of COL2A1, ACAN, SOX9, BMPR2 and miR‐143‐3p of SMSCs were tested by quantitative real‐time polymerase chain reaction (qRT‐PCR). The interaction between miR‐143‐3p and TLR4 was confirmed by luciferase reporter assays. The protein expression levels of related genes were assessed by western blot. Results: High‐throughput sequencing revealed a notable reduction in miR‐143‐3p levels in mechanically stressed SMSCs. Gain‐ or loss‐of‐function strategies introduced by lentivirus demonstrated that miR‐143‐3p overexpression hindered chondrogenic differentiation, whereas its knockdown promoted this process. Bioinformatics scrutiny and luciferase reporter assays pinpointed a potential binding site for miR‐143‐3p within the 3′‐UTR of bone morphogenetic protein receptor type 2 (BMPR2). MiR‐143‐3p overexpression decreased BMPR2 expression and phosphorylated Smad1, 5 and 8 levels, while its inhibition activated BMPR2‐Smad pathway. Conclusion: This study elucidated that miR‐143‐3p negatively regulates SMSCs chondrogenic differentiation through the BMPR2‐Smad pathway under mechanical tensile stress. The direct targeting of BMPR2 by miR‐143‐3p established a novel dimension to our understanding of mechano‐transduction mechanism during SMSC chondrogenesis. This understanding is crucial for advancing strategies in articular cartilage regeneration. [ABSTRACT FROM AUTHOR]

The mechanical stress environment in the temporomandibular joint (TMJ) is constantly changing due to daily mandibular movements. Therefore, TMJ tissues, such as condylar cartilage, the synovial membrane and discs, are influenced by different magnitudes of mechanical stimulation. Moderate mechanical stimulation is beneficial for maintaining homeostasis, whereas abnormal mechanical stimulation leads to degeneration and ultimately contributes to the development of temporomandibular joint osteoarthritis (TMJOA), which involves changes in critical signaling molecules. Under abnormal mechanical stimulation, compensatory molecules may prevent degenerative changes while decompensatory molecules aggravate. In this review, we summarize the critical signaling molecules that are stimulated by moderate or abnormal mechanical loading in TMJ tissues, mainly in condylar cartilage. Furthermore, we classify abnormal mechanical stimulation-induced molecules into compensatory or decompensatory molecules. Our aim is to understand the pathophysiological mechanism of TMJ dysfunction more deeply in the ever-changing mechanical environment, and then provide new ideas for discovering effective diagnostic and therapeutic targets in TMJOA. [ABSTRACT FROM AUTHOR]

Aim: To explore whether ultrasound (US) can be employed to identify the underlying characteristics associated with pain in patients with podagra by evaluating the relationship between ultrasound findings and clinical pain. Material and methods: Patients with podagra were recruited and grouped into a pain group (G1, 82 patients) and a non pain group (G2, 123 patients). US features were collected and compared. US data were analyzed by binary logistic regression analysis and ROC analysis. Interobserver reliability was assessed, too. Results: A total of 205 patients (196 male and 9 female) were enrolled in this study. In multivariate analysis, the thickness of the synovium (OR=1.928, CI=1.074-3.463), CD (color Doppler) signal of the synovium (OR=1.458, CI=1.011-2.103), and CD signal of the tophi (OR=1.576, CI=1.142-2.177) were identified as risk factors for clinical pain. Areas under the ROC curves (AUC) were 0.713, 0.686 and 0.641 for the three indicators, respectively. The best cutoff points were 1 mm for the thickness of the synovium, grade 1 for the CD signal of the synovium and grade 2 for the CD signal of the tophi. Conclusions: Ultrasound can provide valuable information for determining underlying features associated with pain in patients with podagra. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (OA) poses a significant health care burden globally, necessitating innovative therapeutic approaches. CCoat, a novel poly(2-[methacryloyloxy]ethyl phosphorylcholine) (pMPC)ylated liposome device, protects the cartilage surface of the joint from mechanical wear through an entropy-favored process. Two preclinical studies were performed to explore the safety of CCoat following repeated intra-articular (IA) injections into the knee joint (i.e., femorotibial joint) in Sprague-Dawley rats. The studies involved 2 or 3 IA injections, at an interval of 2 or 3 weeks, and an observation period of 1 or 13 weeks after the last injection. Assessments included clinical, histopathological, and immunofluorescent evaluations. In study 1, no mortality or abnormal clinical signs occurred. At 1 week post last injection, histopathology revealed minimal vacuolated macrophages beneath the synovial membrane, predominantly M2-like, indicating a nonadverse response. Immunofluorescent staining supported M2-like macrophage predominance. Study 2 confirmed these findings with no systemic effects over 13 weeks. Statistical analyses indicated no significant differences in body weight, clinical pathology, or organ weights compared with controls. Results affirming the safety of pMPCylated liposomes following repeated IA injections in rat. This novel lubricant coating approach shows promise in OA therapy, with this safety assessment supporting its potential clinical application. [ABSTRACT FROM AUTHOR]

With the rise in longevity within the population, medicine continues to encounter fresh hurdles necessitating prompt actions, among which are those associated with hip joint aging. Age-related arthropathies encompass damage to bones' articulating extremities and their supporting structures, such as articular cartilage, and alterations in the quantity and quality of synovial fluid. This study aims to summarize the biomolecular methods of hip joint evaluation focused on its vascularization, using data correlated with biomolecular research on other joints and tissues, in order to reach an objective opinion of the study prospects in this field. Following a retrospective study on most modern biomolecular research methods on the synovium, the capsule, and the articular cartilage of the hip joint, we have hereby concretized certain future research directions in this field that will improve the qualitative and morphofunctional management of the hip joint at an advanced age, even within population categories at risk of developing various degenerative joint pathologies. [ABSTRACT FROM AUTHOR]

Synovial chondromatosis (SC) is a disorder of the synovium characterized by the formation of osteochondral nodules within the synovium. This study aimed to identify the abnormally differentiated progenitor cells and possible pathogenic signaling pathways. Loose bodies and synovium were obtained from patients with SC during knee arthroplasty. Single-cell RNA sequencing was used to identify cell subsets and their gene signatures in SC synovium. Cells derived from osteoarthritis (OA) synovium were used as controls. Multi-differentiation and colony-forming assays were used to identify progenitor cells. The roles of transcription factors and signaling pathways were investigated through computational analysis and experimental verification. We identified an increased proportion of CD34+ sublining fibroblasts in SC synovium. CD34+CD31− cells and CD34−CD31− cells were sorted from SC synovium. Compared with CD34− cells, CD34+ cells had larger alkaline phosphatase (ALP)-stained area and calcified area after osteogenic induction. In addition, CD34+ cells exhibited a stronger tube formation ability than CD34− cells. Our bioinformatic analysis suggested the expression of TWIST1, a negative regulator of osteogenesis, in CD34− sublining fibroblasts and was regulated by the TGF-β signaling pathway. The experiment showed that CD34+ cells acquired the TWIST1 expression during culture and the combination of TGF-β1 and harmine, an inhibitor of Twist1, could further stimulate the osteogenesis of CD34+ cells. Overall, CD34+ synovial fibroblasts in SC synovium have multiple differentiation potentials, especially osteogenic differentiation potential, and might be responsible for the pathogenesis of SC. [ABSTRACT FROM AUTHOR]

A 15-year-old patient with metastatic synovial sarcoma conveyed to his palliative care physician that his dying wish was to start gender-affirming hormone therapy. His medical team was able to identify resources to support both him and his family as they navigated the immense difficulty of a cancer diagnosis and began to understand their child's gender identity. Literature on the care of gender diverse pediatric patients with terminal illness is minimal, but applications from adult literature, and research on supporting gender diverse adolescents more broadly, provided guidance for palliative care, oncology, and gender-affirming care teams. We believe that honoring and supporting the gender identity of adolescents with terminal illness is an essential aspect of end-of-life care. This case report outlines challenges faced by multidisciplinary pediatric team members who provided gender-affirming care for aminor under hospice care and amplifies the need for future research and guidelines pertinent to this patient population. [ABSTRACT FROM AUTHOR]

Background: Oral mucoceles (OMs) are common cystic lesions seen mainly on the lower lip in young males. Histologically, OMs show variegated features such as clear cell changes, myxoglobulosis, calcifications, and papillary synovial metaplasia (PSM)‐like changes. The aim of the present paper is to morphometrically analyze PSM‐like changes seen in OMs. Methodology: Seventy‐two cases of histologically proven OMs were retrospectively retrieved and divided into two groups: group I without PSM‐like changes and group II with PSM‐like changes. The internal area was measured using Image J software. SPSS version 26 was used to analyze the data. Results: There were 50 cases in group I (mean age 19.23 years) and 22 cases in group II (mean age 30.25 years). The lower lip was the most commonly affected site for both groups. The mean age in group II was significantly higher than group I. In contrast, the mean internal area was significantly higher in group I. Conclusion: We speculate that PSM‐like changes in OMs represent an incomplete repair phenomenon. Knowledge of such an innocuous process is essential for differentiation from malignant histopathological mimickers. [ABSTRACT FROM AUTHOR]

Objectives: Anterior cruciate ligament (ACL) tears are common in the adolescent athletic population. While ACL reconstruction (ACLR) enjoys largely good clinical results, there is clear variability in patient outcomes that cannot be easily explained by surgical technique. In particular, the occurrence of arthrofibrosis, muscular dysfunction, failure to return to sport and even post-traumatic osteoarthritis are difficult to predict based on demographic parameters. There is ample evidence in animal models that synovial inflammation plays a critical role in the development of joint dysfunction after ligament injury, however the role of synovial inflammation in a clinical ACL population has not been studied previously. Adolescents provide an ideal population in which to study post-ACL joint dysfunction as they typically have no pre-existing joint degeneration. We hypothesized that higher synovial immune cell infiltration at the time of ACLR would correlate with worse clinical outcomes (e.g., early loss of motion or arthrofibrosis). To investigate this hypothesis, flow cytometry of synovial samples provided a snapshot of the cellular composition of the synovium, scRNA-seq comprehensively examined a subset of those samples, and correlations with patient-reported clinical outcomes were analyzed. Methods: Patients aged 12-18 years undergoing primary ACLR were enrolled in an IRB-approved prospective study and demographic/injury information collected. At the time of surgery, an arthroscopic synovial biopsy from the prefemoral synovium was digested into a single cell suspension for immune profiling by multicolor flow cytometry and scRNA-seq. Flow cytometry data (n = 17) was acquired on a multi-channel flow cytometer and then analyzed by Principle Component Analysis (PCA) and hierarchical clustering to group the patients by their synovial immune cell profile. Some cells from 6 of the 17 samples were also used for scRNA-seq. Droplet barcoding of cells, RNA library construction, and sequencing of 41,842 cells total was followed generation of t-SNE and UMAP visualizations. Cells were identified by known cell type markers and prevalence analyzed via two-way ANOVA. Clinical outcomes were collected from 2-week, 6-week, 3-month, 6-month, and final postoperative clinical visits (range of motion, complications) and from patient surveys (IKDC, ACL-RSI). Statistical analysis of demographic/injury variables and clinical outcomes included mixed-effects longitudinal analysis, ANOVA, linear regression, and Pearson/Spearman correlations. Results: Seventeen patients were enrolled (9 female/8 male) with a mean follow-up of 8.9 ± months. Analysis of flow cytometry immune profiling revealed three clusters/immunotypes explaining 92.62% of the variation between patients (Fig. 1). There were no significant differences in age, sex, or concomitant meniscal/chondral injury between clusters. The immune cell profile of Type 3 indicated significantly higher immune cell infiltration into the synovium (45% ± 11%, p < 0.005), particularly of adaptive immune cells. Type 1 had lower immune cell infiltration (31.6% ± 3.8%) and adaptive immune contribution while Type 2 was intermediate. Type 1 also had a greater time between injury and surgery (median 99 days, 51-989; p < 0.05) than Type 2 (median 32 days, 21-38) and Type 3 (median 32 days, 13-42), and Type 1 synovium contained more mast cells (2.7 ± 0.78% of total cells, p < 0.05) than Type 2 (1.0 ± 0.39 %) and Type 3 (1.3 ± 0.82%). When a subset of these synovium tissues (n = 6) were analyzed via scRNA-seq, 25 cell types were identified overall (Fig. 2) with immunotype 3 trending towards more T cells and B cells, and a higher CD8+ to CD4+ T cell ratio. The overall immune profile pattern shown as a heatmap (Fig. 3) suggests that Type 3 synovium may experience higher adaptive inflammation compared to Type 1. The mean 6-month IKDC scores (n = 17, p = 0.99) were 77.93 ± 8.19 for Type 1, 78.55 ± 7.85 for Type 2, and 79.88 ± 14.44 for Type 3 (Fig. 4A). The mean 6-month ACL-RSI scores (n = 15, p = 0.33) were 78.58 ± 15.4 for Type 1, 72.33 ± 11.8 for Type 2, and 57.83 ± 26.4 for Type 3 (Fig. 4A). Knee range of motion was significantly worse for Type 3 in both extension and flexion (Fig. 4B-C, mixed effects p < 0.05), particularly in the 2-week to 3-month post-op range. Additionally, no complications occurred for patients in Type 1, one case of very mild loss of extension (< 3 degrees) was observed in Type 2, while significant complications occurred in Type 3 including one ACL re-rupture requiring revision and a separate case of arthrofibrosis with a 30-degreeflexion contracture requiring lysis of adhesions. Conclusions: Our pilot study provides the first analysis of immune cell behavior in the synovium of ACL injured knees at the time of ACLR. Three immunotypes were discovered. Type 1, the cluster with the lowest overall and adaptive inflammatory response corresponded to patients with a mean 3-month delay between injury and surgery. These patients also had the best clinical outcomes. Type 2 and Type 3 clusters included more acute surgeries (~ 1-month post-injury). However, Type 3 showed significantly higher inflammatory infiltrate, adaptive immune cell presence, and a prevalence of cytotoxic T cells. In turn, these patients had decreased early range of motion, lower ACL-RSI scores at 6 months, and higher incidence of surgical arthrofibrosis and graft failure. Thus, while time between injury and surgery is a contributor to inflammation levels at the time of ACLR, there are intrinsic, patient-specific differences in their acute inflammatory response that also contribute. Understanding these patient-specific differences in a larger prospective cohort might help guide targeted prevention strategies for arthrofibrosis, failure to return to sport, or even post-traumatic osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective: We previously reported that CD14+ dendritic‐shaped cells exhibit a dendritic morphology, engage in pseudo‐emperipolesis with lymphocytes, and express CD90 in the perivascular areas of rheumatoid arthritis (RA) synovial tissues. However, it remains unclear whether these CD14highCD90intermediate(int) cells function as dendritic cells. In this study, we investigated the dendritic cell–differentiation potential of CD14highCD90int cells. Methods: The localization and number of CD14highCD90int cells in RA synovial tissues and peripheral blood were examined. The dendritic cell–differentiation potential of CD14highCD90int cells was examined by measuring interleukin‐6 and tumor necrosis factor‐α levels in the supernatant and CD83 and human leukocyte antigen (HLA)‐DR expression in the cells after induction of dendritic cell differentiation. Synovial cells were co‐cultured with lymphocytes, and the activation of these cells was examined. Results: CD14highCD90int cells were abundant in RA synovial tissues, including the sublining layer and the pannus areas. Patients with untreated and active RA had significantly higher percentages of CD14highCD90int cells in the peripheral blood and synovial tissues. In RA synovial cells, inflammatory cytokine levels increased with dendritic cell–differentiation culture, but CD83 and HLA‐DR expression were significantly increased in the CD14highCD90int cell group. When co‐cultured with lymphocytes, cell numbers and inflammatory cytokine levels significantly increased in both groups of synovial cells after dendritic cell induction. Conclusion: CD14+ cells migrate and spread from the circulating blood to RA synovial tissues while expressing CD90, and CD14highCD90int cells in contact with lymphocytes differentiate into HLA‐DR+ dendritic cells, which contribute to chronic inflammation in RA. [ABSTRACT FROM AUTHOR]

Background: This study aimed to validate alterations in the gene expression of DNA methylation-related enzymes and global methylation in the peripheral blood mononuclear cell (PBMC) and synovial tissues of animal hip osteoarthritis (OA) models. Methods: Animals were assigned to the control (no treatment), sham (25 µL of sterile saline), and OA (25 µL of sterile saline and 2 mg of monoiodoacetate) groups. Microcomputed tomography scan, histopathological assessment and pain threshold measurement were performed after induction. The mRNA expression of the DNA methylation machinery genes and global DNA methylation in the PBMC and hip synovial tissue were evaluated. Results: The OA group presented with hip joint OA histopathologically and radiologically and decreased pain threshold. The mRNA expression of DNA methyltransferase (Dnmt 3a), ten–eleven translocation (Tet) 1 and Tet 3 in the synovial tissue of the OA group was significantly upregulated. Global DNA methylation in the synovial tissue of the OA group was significantly higher than that of the control and sham groups. Conclusions: The intra-articular administration of monoiodoacetate induced hip joint OA and decreased pain threshold. The DNA methylation machinery in the synovial tissues of hip OA was altered. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common form of arthritis, characterized by osteophyte formation, cartilage degradation, and structural and cellular alterations of the synovial membrane. Activated fibroblast-like synoviocytes (FLS) of the synovial membrane have been identified as key drivers, secreting humoral mediators that maintain inflammatory processes, proteases that cause cartilage and bone destruction, and factors that drive fibrotic processes. In normal tissue repair, fibrotic processes are terminated after the damage has been repaired. In fibrosis, tissue remodeling and wound healing are exaggerated and prolonged. Various stressors, including aging, joint instability, and inflammation, lead to structural damage of the joint and micro lesions within the synovial tissue. One result is the reduced production of synovial fluid (lubricants), which reduces the lubricity of the cartilage areas, leading to cartilage damage. In the synovial tissue, a wound-healing cascade is initiated by activating macrophages, Th2 cells, and FLS. The latter can be divided into two major populations. The destructive thymocyte differentiation antigen (THY)1- phenotype is restricted to the synovial lining layer. In contrast, the THY1+ phenotype of the sublining layer is classified as an invasive one with immune effector function driving synovitis. The exact mechanisms involved in the transition of fibroblasts into a myofibroblast-like phenotype that drives fibrosis remain unclear. The review provides an overview of the phenotypes and spatial distribution of FLS in the synovial membrane of OA, describes the mechanisms of fibroblast into myofibroblast activation, and the metabolic alterations of myofibroblast-like cells. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune condition frequently found in rheumatological patients that sometimes raises diagnosis and management problems. The pathogenesis of the disease is complex and involves the activation of many cells and intracellular signaling pathways, ultimately leading to the activation of the innate and acquired immune system and producing extensive tissue damage. Along with joint involvement, RA can have numerous extra-articular manifestations (EAMs), among which lung damage, especially interstitial lung disease (ILD), negatively influences the evolution and survival of these patients. Although there are more and more RA-ILD cases, the pathogenesis is incompletely understood. In terms of genetic predisposition, external environmental factors act and subsequently determine the activation of immune system cells such as macrophages, neutrophils, B and T lymphocytes, fibroblasts, and dendritic cells. These, in turn, show the ability to secrete molecules with a proinflammatory role (cytokines, chemokines, growth factors) that will produce important visceral injuries, including pulmonary changes. Currently, there is new evidence that supports the initiation of the systemic immune response at the level of pulmonary mucosa where the citrullination process occurs, whereby the autoantibodies subsequently migrate from the lung to the synovial membrane. The aim of this paper is to provide current data regarding the pathogenesis of RA-associated ILD, starting from environmental triggers and reaching the cellular, humoral, and molecular changes involved in the onset of the disease. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA. Activated B cells and T cells accumulate within joints of patients with rheumatoid arthritis. Here, the authors use single-cell transcriptome and repertoire profiling to identify clonally expanded synovial B cells and T cells and define their phenotypes and predicted cell-cell interactions. [ABSTRACT FROM AUTHOR]

Here, we describe a case of a 5-year-old show-jumping stallion presented with severe lameness, swelling, and pain on palpation of the left metacarpophalangeal joint (MCj). Diagnostic imaging revealed full and partial-thickness articular defects over the lateral condyle of the third metacarpus (MC3) and the dorsolateral aspect of the first phalanx (P1). After the lesion's arthroscopic curettage, the patient was subjected to an innovative regenerative treatment consisting of two intra-articular injections of equine synovial membrane mesenchymal stem/stromal cells (eSM-MSCs) combined with umbilical cord mesenchymal stem/stromal cells conditioned medium (UC-MSC CM), 15 days apart. A 12-week rehabilitation program was accomplished, and lameness, pain, and joint effusion were remarkably reduced; however, magnetic resonance imaging (MRI) and computed tomography (CT) scan presented incomplete healing of the MC3's lesion, prompting a second round of treatment. Subsequently, the horse achieved clinical soundness and returned to a higher level of athletic performance, and imaging exams revealed the absence of lesions at P1, fulfillment of the osteochondral lesion, and cartilage-like tissue formation at MC3's lesion site. The positive outcomes suggest the effectiveness of this combination for treating full and partial cartilage defects in horses. Multipotent mesenchymal stem/stromal cells (MSCs) and their bioactive factors compose a novel therapeutic approach for tissue regeneration and organ function restoration with anti-inflammatory and pro-regenerative impact through paracrine mechanisms. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Toevaluate theeffects of a gene transfer approach to IL-12 inhibition inan equineosteochondral chip fragment model of joint injury using a self-complementaryadeno-associated virus with interleukin receptorantagonist transgene cassette (scAAVIL-lra), as posttraumatic osteoarthritis in horses, similar to people, is a significant clinical problem. ANIMALS: 16 horses were utilized for the study. METHODS All horses had an osteochondral chip fragment induced arthroscopically in one middle carpal joint while the contralateral joint was sham operated. Eight horses received either scAAVIL-lra or saline in the osteoarthritis joint. Horses were evaluated over 70 days clinically (lameness, imaging, and biomarker analysis) and euthanized at 70 days and evaluated grossly, with imaging and histopathology. RESULTS: The following findings were statistically significant. Injection of scAAVIL-lra resulted in high synovial fluid levels of IL-lra (0.5 to 9 Ug/mL) throughout the duration of the experiment (70 days). Over the duration, we observed scAAVIL-lra to improve lameness (lameness score relative improvement of 1.2 on a scale of 0 to 5), cause suppression of prostaglandin E2 (a relative decline of 30 pg/mL), and result in histological improvement in articular cartilage (decreased chondrocyte loss and chondrone formation) and subchondral bone (less osteochondral splitting and osteochondral lesions). Within the synovial membrane of scAAVIL-lra-treated joints, we also observed perivascular infiltration with CD3-positive WBCs, suggesting Iymphocytic T-cell perivascular infiltration commonly observed with viral transduction. CLINICAL RELEVANCE: These data provide support for further evaluation and optimization of scAAVIL-lra gene therapy to treat equine osteoarthritis. [ABSTRACT FROM AUTHOR]

Objective: The specific role of fibroblast‐like synoviocytes (FLSs) in the pathogenesis of rheumatoid arthritis (RA) is still not fully elucidated. This study aimed to explore the molecular mechanisms of epigenetic pathways, including three epigenetic factors, microRNA (miRNA)‐22 (MIR22), ten‐eleven translocation methylcytosine dioxygenase 3 (TET3), and MT‐RNR2 like 2 (MTRNR2L2), in RA‐FLSs. Methods: The expression of MIR22, TET3, and MTRNR2L2 in the synovium of patients with RA and arthritic mice were determined by fluorescence in situ hybridization, quantitative polymerase chain reaction (qPCR), immunohistochemistry, and Western blot. Mir22−/− and Tet3+/− mice were used to establish a collagen antibody–induced arthritis (CAIA) model. Mir22 angomir and Tet3 small interfering RNA (siRNA) were used to illustrate the therapeutic effects on arthritis using a collagen‐induced (CIA) model. Bioinformatics, luciferase reporter assay, 5‐hydroxymethylcytosine (5hmC) dot blotting, chromatin immunoprecipitation–qPCR, and hydroxymethylated DNA immunoprecipitation were conducted to show the direct repression of MIR22 on the TET3 and transcriptional activation of TET3 on MTRNR2L2. Results: The Mir22−/− CAIA model and RA‐FLS–related in vitro experiments demonstrated the inhibitory effect of MIR22 on inflammation. MIR22 can directly inhibit the translation of TET3 in RA‐FLSs by binding to its 3′ untranslated region in TET3. The Tet3+/− mice–established CAIA model showed less severe symptoms of arthritis in vivo. In vitro experiments further confirmed the proinflammatory effect of TET3 in RA. In addition, the CIA model was used to validate the therapeutic effects of Mir22 angomir and Tet3 siRNA. Finally, TET3 exerts its proinflammatory effect by promoting 5hmC production in the promoter of its target MTRNR2L2 in RA‐FLSs. Conclusion: The key role of the MIR22‐TET3‐MTRNR2L2 pathway in RA‐FLSs provided an experimental basis for further studies into the pathogenesis and related targets of RA from the perspective of FLSs. [ABSTRACT FROM AUTHOR]

Calcium pyrophosphate dehydrate (CPPD) crystals are found in the synovial fluid of patients with articular chondrocalcinosis or sometimes with osteoarthritis. In inflammatory conditions, the synovial membrane (SM) is subjected to transient hypoxia, especially during movement. CPPD formation is supported by an increase in extracellular inorganic pyrophosphate (ePPi) levels, which are mainly controlled by the transporter Ank and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We demonstrated previously that transforming growth factor (TGF)-β1 increased ePPi production by inducing Ank and Enpp1 expression in chondrocytes. As the TGF-β1 level raises in synovial fluid under hypoxic conditions, we investigated whether hypoxia may transform SM as a major source of ePPi production. Synovial fibroblasts and SM explants were exposed to 10 ng/mL of TGF-β1 in normoxic or hypoxic (5% O2) culture conditions. Ank and Enpp1 expression were assessed by quantitative PCR, Western blot and immunohistochemistry. ePPi was quantified in culture supernatants. RNA silencing was used to define the respective roles of Ank and Enpp1 in TGF-β1-induced ePPi generation. The molecular mechanisms involved in hypoxia were investigated using an Ank promoter reporter plasmid for transactivation studies, as well as gene overexpression and RNA silencing, the respective role of hypoxia-induced factor (HIF)-1 and HIF-2. Our results showed that TGF-β1 increased Ank, Enpp1, and therefore ePPi production in synovial fibroblasts and SM explants. Ank was the major contributor in ePPi production compared to ENPP1. Hypoxia increased ePPi levels on its own and enhanced the stimulating effect of TGF-β1. Hypoxic conditions enhanced Ank promoter transactivation in an HIF-1-dependent/HIF-2-independent fashion. We demonstrated that under hypoxia, SM is an important contributor to ePPi production in the joint through the induction of Enpp1 and Ank. These findings are of interest as a rationale for the beneficial effect of anti-inflammatory drugs on SM in crystal depositions. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment. In RA synovium, dendritic cells present self-antigens to activate the whole inflammatory pathway. Inhibiting antigen-presentation could effectively block the initiation of entire pathway. However, the downstream macrophages secrete high levels of pro-inflammatory cytokines, while excessively proliferated synovial fibroblasts (FLS) are responsible for hypoxia microenvironment, cytokine/chemokine release, bone/cartilage erosion, thus constructing an immune cycle independent of antigen-presentation together with macrophages. In this timely research, we successfully developed an implantable and pH-sensitive peptide hydrogel loading siRNA/methotrexate-polyethyleneimine (siMP: siCD86MP, sip65MP, sip38MP) and bismuthene nanosheet/methotrexate-polyethyleneimine (BiMP). siCD86MP can reduce the protein level of co-stimulatory molecule CD86 to block the initiation of inflammatory pathway. sip65MP and sip38MP can inhibit NF-κB and MAPK-p38 pathways in macrophages and FLS to ameliorate secretion of cytokines and MMPs, fundamentally blocking inflammatory circulation. Meanwhile, reduction in anti-apoptosis property of FLS induced by siMP had the synergistic effect with PDT and PTT of BiMP for FLS elimination, effectively ameliorating synovium microenvironment. After injection into synovium, the hydrogel responded to the acidic microenvironment and served as a drug reservoir for sustained drug release, while reducing systematic toxicity of cationic nanoparticles. The inherent retention capacity of hydrogel enabled nanoparticles to bypass the tissue barrier and achieve precise targeting. This brand-new drug delivery system combines modulating inflammation pathways from beginning to end by RNAi and eliminating FLS by phototherapy for improving synovium microenvironment together, providing a robust strategy for RA treatment. [Display omitted] • siRNA modulated cascade immune activation through inhibiting upstream antigen-presentation and downstream inflammatory circulation. • Bismuthene nanosheets exerted efficient PDT&PTT therapy to eliminate FLS for alleviating hypoxic synovium microenvironment. • Modulation of cascade immune activation and alleviating hypoxia microenvironment can synergistically treat RA. • Nap Hydrogel possessed excellent biocompatibility, injectability, self-healing, pH responsiveness, synovium targeting and retention. [ABSTRACT FROM AUTHOR]

One of the most common musculoskeletal disorders, osteoarthritis (OA), causes worldwide disability, morbidity, and poor quality of life by degenerating articular cartilage, modifying subchondral bone, and inflaming synovial membranes. OA pathogenesis pathways must be understood to generate new preventative and disease-modifying therapies. In recent years, it has been acknowledged that gut microbiota (GM) can significantly contribute to the development of OA. Dysbiosis of GM can disrupt the "symphony" between the host and the GM, leading to a host immunological response that activates the "gut–joint" axis, ultimately worsening OA. This narrative review summarizes research supporting the "gut–joint axis" hypothesis, focusing on the interactions between GM and the immune system in its two main components, innate and adaptive immunity. Furthermore, the pathophysiological sequence of events that link GM imbalance to OA and OA-related pain is broken down and further investigated. We also suggest that diet and prebiotics, probiotics, nutraceuticals, exercise, and fecal microbiota transplantation could improve OA management and represent a new potential therapeutic tool in the light of the scarce panorama of disease-modifying osteoarthritis drugs (DMOADs). Future research is needed to elucidate these complex interactions, prioritizing how a particular change in GM, i.e., a rise or a drop of a specific bacterial strain, correlates with a certain OA subset to pinpoint the associated signaling pathway that leads to OA. [ABSTRACT FROM AUTHOR]

The article discusses the clinical efficacy of abatacept, a biologic drug used to treat rheumatoid arthritis (RA), in Chinese patients. The study conducted at Zhejiang Provincial People's Hospital involved 53 RA patients who received abatacept treatment for at least 3 months. Results showed a significant decrease in disease activity scores and synovial membrane thickness after treatment, with a more pronounced effect observed in elderly patients. However, the study acknowledges limitations such as a small sample size and short duration, emphasizing the need for further research to validate these findings. [Extracted from the article]

The impact of mild synovitis on the chondrogenic environment in the joint pertaining to cartilage repair is often neglected. In this study, 21 synovial samples were collected from foot surgeries for histology and isolation of fibroblast-like synoviocytes (FLSs). Of the 21 samples, 13 were normal and eight were mild synovitis, according to their synovitis scores. In mild synovitis, CD3+ lymphocytes were increased in the sublining layer. When chondrocytes were cultured and treated with the conditioned medium produced by FLSs, their glycosaminoglycan production was negatively correlated with the synovitis scores of the synovium, from which FLSs were isolated. In conclusion, mild synovitis in common joint conditions compromises the process of chondrogenesis, via inhibiting chondrocyte matrix production by FLSs. The results suggest that the concomitant synovitis, even being mild, could significantly alter the joint environment for chondrogenesis and impair the outcome of cartilage repair. [ABSTRACT FROM AUTHOR]