Synovial Joints Research Articles

Collagen triple helix repeat-containing 1 protein: an emerging biomarker and its influence on the clinical and sonographic disease severity in Egyptian medicated female rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of synovial joints, with a multifactorial etiology. Collagen triple helix repeat-containing 1 protein (CTHRC1) is a biomarker produced by fibroblast-like synoviocytes, which was shown to be highly expressed in RA patients. The study aimed to measure serum CTHRC1 level in female RA patients currently on medical treatment and its influence on the clinical and sonographic severity of the disease.ResultsThe patients’ mean age was 43.39 ± 8.55 years and median RA disease duration of 5.5 (0.33–20) years. RA patients showed significantly higher serum CTHRC1 level [89.71 ng/ml (53.95–353.45)] in comparison to controls [87.38 ng/ml (44.47–110.3)] (U = 430, P = 0.014). Furthermore, higher serum CTHRC1 levels were recorded in seropositive versus seronegative patients (U = 76, P = 0.022) and in RA patients with severe disease activity compared to those with lower disease activity (H = 9.79, P = 0.007). Furthermore, serum CTHRC1 levels were lower in RA patients receiving biological therapy compared to those receiving conventional therapy; however, this difference did not reach statistical significance.Significant positive correlations were found between CTHRC1 and disease activity, acute-phase reactants, serological markers, functional assessment, fatigue, and erosions detected by ultrasound, while a significant negative correlation was recorded between CTHRC1 and duration of biologic intake (rs = − 0.45, P = 0.036). Furthermore, on multivariate linear regression analysis, serum CTHRC1 was the only significant predictor for higher disease activity (P = 0.028, B = 0.009, 95% CI 0.001 to 0.017).ConclusionRA patients showed higher CTHRC1 serum levels compared to healthy controls, especially those with seropositivity and highly active disease. Furthermore, it was positively associated with poor patient functional outcome, fatigability, and erosive findings by ultrasound, thus suggesting that serum CTHRC1 can be a good predictor for high RA disease activity and possibly severity. Moreover, biological therapy could influence serum CTHRC1 levels in these patients.

GZMK Facilitates Experimental Rheumatoid Arthritis Progression by Interacting with CCL5 and Activating the ERK Signaling.

Synovial over-proliferation is a key event in the progression of rheumatoid arthritis (RA) disease. Ferroptosis may be essential for maintaining the balance between synovial proliferation and death. This study aimed to investigate the molecular mechanisms mediating the activation and ferroptosis of collagen-induced arthritis(CIA)-synovial fibroblasts (SFs). Differentially expressed genes (DEGs) in the synovial tissues of CIA rats and normal rats were screened through sequencing. The GSE115662 dataset from the GEO database was analyzed and screened for DEGs. The viability, proliferation, migration, invasion, cell cycle, and apoptosis of CIA-SFs were analyzed by cell counting kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, transwell migration, and invasion assays. The ferroptosis of CIA-SFs was assessed using matching reagent kits to detect indicators like reactive oxygen species, ferrous iron, malondialdehyde, glutathione, and superoxide dismutase. The interaction between Granzyme K (GZMK) and C-C motif chemokine 5 (CCL5) was determined by coimmunoprecipitation assay. We found abnormal GZMK expression in the GSE115662 database and mRNA sequencing data. GZMK was overexpressed in CIA-SFs, and GZMK promoted cell proliferation, migration, invasion, inflammation, and decreased cell apoptosis and ferroptosis in CIA-SFs. GZMK could interact with CCL5 to activate the ERK signaling. GZMK and CCL5 knockdown improved by reducing arthritis scores, redness and swelling of paws, and pathological changes in joint synovium of CIA rats. CCL5 overexpression reversed the effects of GZMK silencing on CIA-SFs cell proliferation, migration, invasion, apoptosis, and ferroptosis. We confirmed that GZMK accelerated experimental rheumatoid arthritis progression by interacting with CCL5 and activating the ERK signaling.

Hyaluronic acid modified prussian blue analogs/TiO₂ janus nanostructures through efficient charge separation to enhance photocatalytic-driven dual gas for achieve multimodal treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by the abnormal proliferation of fibroblast-like synoviocytes and changes in the joint synovium, including elevated reactive oxygen species, decreased pH, and reduced oxygen content. In this study, we synthesized a novel nanocomposite material, namely HA-PBA-TiO2 Janus nanocomposite, by in situ etching in prussian blue analogs doped with Co and Ni, followed by the growth of TiO2 nano-flowers and encapsulation in hyaluronic acid. When these janus nanoparticles diffused to the inflammatory sites of RA, they exhibited outstanding photocatalytic water-splitting ability under 660 nm laser irradiation, generating H2 and O2. This capability helps ameliorate the hypoxic microenvironment at RA inflammatory sites by eliminating reactive oxygen species (ROS) and enhancing antioxidation and oxygenation. Furthermore, owing to the doping of Co and Ni, HA-PBA-TiO2 exhibits photothermal conversion capability, which significant damage to FLS upon exposure to 660 nm laser irradiation, thereby controlling their aberrant proliferation. Through a series of in vitro and in vivo experiments, we validated the significant therapeutic efficacy of HA-PBA-TiO2 in treating RA, highlighting its broad prospects for application.

Application of superb microvascular imaging technology in clinical disease activity of rheumatoid arthritis.

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. 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. 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). 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 microvesselsin 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.

ITGA5+ synovial fibroblasts orchestrate proinflammatory niche formation by remodelling the local immune microenvironment in rheumatoid arthritis.

To investigate the phenotypic heterogeneity of tissue-resident synovial fibroblasts and their role in inflammatory response in rheumatoid arthritis (RA). We used single-cell and spatial transcriptomics to profile synovial cells and spatial gene expressions of synovial tissues to identify phenotypic changes in patients with osteoarthritis, RA in sustained remission and active state. Immunohistology, multiplex immunofluorescence and flow cytometry were used to identify synovial fibroblasts subsets. Deconvolution methods further validated our findings in two cohorts (PEAC and R4RA) with treatment response. Cell coculture was used to access the potential cell-cell interactions. Adoptive transfer of synovial cells in collagen-induced arthritis (CIA) mice and bulk RNA sequencing of synovial joints further validate the cellular functions. We identified a novel tissue-remodelling CD45-CD31-PDPN+ITGA5+ synovial fibroblast population with unique transcriptome of POSTN, COL3A1, CCL5 and TGFB1, and enriched in immunoregulatory pathways. This subset was upregulated in active and lympho-myeloid type of RA, associated with an increased risk of multidrug resistance. Transforming growth factor (TGF)-β1 might participate in the differentiation of this subset. Moreover, ITGA5+ synovial fibroblasts might occur in early stage of inflammation and induce the differentiation of CXCL13hiPD-1hi peripheral helper T cells (TPHs) from naïve CD4+ T cells, by secreting TGF-β1. Intra-articular injection of ITGA5+ synovial fibroblasts exacerbates RA development and upregulates TPHs in CIA mice. We demonstrate that ITGA5+ synovial fibroblasts might regulate the RA progression by inducing the differentiation of CXCL13hiPD-1hi TPHs and remodelling the proinflammatory microenvironments. Therapeutic modulation of this subpopulation could therefore be a potential treatment strategy for RA.

Inflammatory arthropathies: Perspectives from a Portuguese male individual (1574–1834 CE)

AbstractArthropathies are common in past populations and can be categorized into two groups: those with predominant bone production (e.g., osteoarthritis) and those with significant bone loss (e.g., erosive arthropathies). The former is frequent in the archaeological record, whereas the latter are uncommon. We present a Post‐Medieval male individual, recovered in the Convent of the Holy Spirit (Loures, Portugal), with multiple articular and entheseal bone changes, particularly extensive periarticular, marginal, and subchondral erosive processes, often exposing trabecular bone. Proliferative lesions and extensive ankylosis are also observed in the synovial joints. These pathological changes affect both the axial and peripheral skeleton in a polyarticular, bilateral, and asymmetric pattern. Given that the appendicular skeleton, particularly the hands and feet, are the most affected areas, the most probable diagnosis is a peripheral spondyloarthropathy such as psoriatic arthritis or reactive arthritis. This case study is the first archaeological instance of psoriatic arthritis or reactive arthritis described in Portugal, highlighting the importance of a differential diagnosis and the need for reflection when pathological changes characteristics overlap, advocating for a broader diagnostic approach.

Chitosan-based self-healing thermosensitive hydrogel loaded with siHMGB1 for treatment of rheumatoid arthritis via macrophage repolarization.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease marked by immune cell activation, particularly macrophages. An imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages causes synovial inflammation and joint damage, worsening RA. This study presents a biomacromolecular hydrogel delivery system with apoferritin nanoparticles for effective delivery of small interfering high mobility group protein (siHMGB1). The system was designed to promote the polarization of M1 macrophages to the M2 phenotype by downregulating the HMGB1/TLR4/NF-κB-p65 signaling pathway, offering a potential therapeutic approach for the treatment of RA. The oxidized chondroitin sulfate - chitosan - sodium glycerol β - phosphate - Fn/siHMGB1 (OCF/siHMGB1) hydrogel system possessed temperature-sensitive and self-healing properties, enabling the sustained, stable, and efficient release of siHMGB1 at the affected joint. After effective uptake by macrophages, siHMGB1 could effectively repolarize M1-phenotype macrophages to M2-phenotype via the HMGB1/TLR4/NF-κB-p65 signaling pathway both in vitro and in vivo. Additionally, it suppressed the release of pro-inflammatory cytokines and upregulated anti-inflammatory cytokines, which significantly blocked the TLR4/p65-mediated inflammatory signaling. In conclusion, the siHMGB1-loaded hydrogel delivery system designed in this study is effective in treating RA and highlights the potential of gene therapy to induce repolarization of M1 to M2 macrophages for RA treatment.

The association of osteoarthritis with metabolic disorders

Osteoarthritis (OA) is the most common form of synovial joint arthritis that causes chronic pain and disability to a large number of people worldwide. Most often, osteoarthritis affects the joints of the knees, hips, spine and hands. The Global Burden of Disease (GBD, 2021) estimates that osteoarthritis will be the fourth leading cause of disability by 2030, with enormous healthcare costs for treatment, as well as significant indirect costs due to loss of productivity and premature retirement. The aim of our research is to determine in what way prevalent metabolic syndrome is among participants with osteoarthritis of one of the synovial joints (knees, hips, hands), and whether metabolic disorders are a risk factor for the development and worsening of osteoarthritis. A prospective clinical study was conducted at the Public Health Institution Health Center Živinice, from July 2022 to May 2024, on a random sample of 200 participants with a confirmed clinical diagnosis of osteoarthritis (OA), who were divided into a group with metabolic syndrome and a group without metabolic syndrome based on the NCEP ATP III panel criteria for metabolic syndrome. The prevalence of knee osteoarthritis is significantly higher compared to the prevalence of hip and hand osteoarthritis, and it is greater among participants with a higher BMI (in participants with the highest BMI, knee osteoarthritis occurs with a 100% probability) and with the presence of metabolic syndrome, especially in more severe forms, specifically radiologically confirmed osteoarthritis, regardless of age and gender. Unlike OA knees the prevalence of OA hips and hands shows no correlation with BMI and metabolic syndrome. Multiple comparative analysis of differences in the average severity of osteoarthritis of the knee of subjects with normal glycemia / prediabetes / diabetes type 2 it showed a statistically significant difference in the average severity of knee osteoarthritis in subjects with regular blood sugar compared to subjects with prediabetes/diabetes mellitus type 2 regardless of age and gender. This means that with an increase in blood sugar levels, the degree of severity of osteoarthritis of the knee increases, since each subsequent Group has a higher average value of this indicator (p&lt;0.05; CI 95%).

Features of Magnetic Resonance Diagnostics of Tenosynovial Giant Cell Tumor (Pigmented Villonodular Synovitis)

Aim. Demonstrate the features of magnetic resonance diagnostics of tenosynovial giant cell tumor.Materials and Methods. Using magnetic resonance imaging, we identified patients with tenosynovial giant cell tumor of the knee joint, describing the diagnostic features and clinical course of diffuse and local forms of the tumor.Results. Specific MRI patterns of tenosynovial giant cell tumor are hemosiderin deposits, villous and nodular growths of the synovium of the knee joint, joint effusion and bone erosion.Conclusion. Тenosynovial giant cell tumor is a rare mesenchymal neoplasm arising from the synovium of joints and tendon sheaths, disabling young able-bodied people. Magnetic resonance imaging, being the “gold” standard for radiological diagnostics, helps to identify specific patterns.

Effects of moxibustion in improving synovitis in adjuvant arthritis rats by regulating synovial GPR43 and peripheral blood Th17/Treg balance

To observe the effects of moxibustion on G protein-coupled receptor 43 (GPR43) and helper T cell 17 (Th17)/regulatory T cell (Treg) balance in rats with adjuvant arthritis (AA), so as to investigate the partial mechanism of moxibustion therapy on rheumatoid arthritis (RA). A total of 24 Wistar rats were randomly divided into a normal group, a model group and a moxibustion group, with 8 rats in each group. The AA rat model was replicated using wind, cold and moisture environmental factors + Freund's complete adjuvant (CFA) injection method. In the moxibustion group, moxibustion was performed on bilateral "Zusanli" (ST36) and "Shenshu" (BL23) for 20 min/time, once daily, for 21 d. The changes of joint swelling degree (JSD) and arthritis index (AI) were observed in each group of rats. Transmission electron microscopy and HE staining were used to examine changes in the cellular structure of the ankle joint synovial tissue in each group. Western blot analysis was employed to detect the expression levels of GPR43 in the synovial tissue of the ankle joints. Flow cytometry was used to measure the percentages of Treg and Th17 in peripheral blood. ELISA was used to determine the contents of interleukin-10 (IL-10) and transforming growth factor-β 1 (TGF-β1) in serum. Compared with the normal group, the JSD and AI in the model group increased before and after treatment (P<0.01), with significant synovial pathological and ultrastruct ural injury observed. Additionally, compared with the normal group, the expression of GPR43 in the synovial tissue decreased (P<0.01), the Treg percentage in peripheral blood decreased (P<0.01) and the Th17 percentage increased (P<0.01), serum IL-10 and TGF-β1 contents decreased in the model group (P<0.01). Compared with the model group, the moxibustion group exhibited a significant reduction in JSD and AI after treatment (P<0.01), the degree of pathological and ultrastruct ural damage in the synovium decreased, the expression of GPR43 in the synovial tissue increased (P<0.05), the Treg percentage in peripheral blood increased (P<0.01) and the Th17 percentage decreased (P<0.01), serum IL-10 and TGF-β1 contents increased (P<0.01). The relative expression of GPR43 in synovial tissue was positively correlated with the percentage of Treg in peripheral blood (r=0.967, P<0.01). Moxibustion can significantly improve the inflammatory response in the synovial membrane of AA rats. The mechanism may be related to moxibustion restoring the Th17/Treg balance through regulating GPR43.

A compartmentalized microfluidic platform to investigate immune cells cross-talk in rheumatoid arthritis

The dysregulation of the immune system plays a crucial role in the pathogenesis of manyfold diseases, among which we find rheumatoid arthritis (RA), an autoimmune disease characterized by chronic inflammation in synovial joints, leading to pain and disability. Immune cells such as pro-inflammatory macrophages and T helper 1 (Th1) cells drive the inflammatory cascade. Thus, including immune system inin vitromodels is pivotal to recapitulate and better understand the complex interactions between these immune cell subsets and their secreted mediators. Here, a compartmentalized microfluidic platform is presented, for precise confinement of circulating immune cells in organs-on-chip. The integration of innovative normally-closed sieving valves allows, through minimal waste of biological material, to co-culture different immune cell types (e.g. macrophages and Th1). Moreover, the platform allows to stimulate cell subsets separately, and to assess their cross-talk at desired time points. Functional validation of the platform demonstrates its ability to create stable chemotactic gradients, allowing for induction and evaluation of Th1 cells migration. In a proof-of-concept study, the platform allowed to assess Th1 T cells migration towards pro-inflammatory macrophages, thus replicating a characteristic interaction among immune cells triggered during RA onset. These results thus support the suitability of the platform to study immune cells cross-talk and migration phenomena, being potentially applicable to a manyfold immune cell mechanisms, both involved in RA progression and in different immune-mediated pathologies.

Surgical Management of Early Metacarpophalangeal Joint Silicone Implant Fracture in Patient With Rheumatoid Arthritis

Introduction: Metacarpophalangeal (MCP) joint arthroplasty is a common treatment modality to correct ulnar drift, pain, and functional deficits in patients with rheumatoid arthritis, an autoimmune condition targeting the synovium of joints. While silicone MCP joint implants are susceptible to revision in the long term, there is a lack of literature discussing their early breakage. The present case illustrates silicone implant fracture only 10 weeks after MCP arthroplasty—the first instance in the literature to the authors’ knowledge. Materials and Methods: The patient is a 64-year-old female with stage 4 rheumatoid arthritis who underwent right index and middle finger MCP joint arthroplasties using 0-degree silicone implants, radial sagittal band imbrication on these digits, and right ring and small finger extensor tendon centralization at the MCP joint. Results: During the 10th postoperative week, the patient presented with atraumatic middle finger pain and ulnar deviation. Imaging revealed a right middle finger MCP implant fracture at the distal stem, which underwent successful revision using a 30-degree flexed implant and index and middle extensor tendon centralization. Discussion: Nineteen months after revision surgery, the patient continues to have no pain and an improved range of motion. Ultimately, we are hopeful that the flexed silicone implant will last the patient's lifetime.

A natural composite hydrogel laden with mesenchymal stromal cells for osteochondral repair: Comparison between casting and 3D bioprinting

Synovial joints, and particularly the osteochondral unit, are prone to lesions, with high risk of degeneration towards osteoarthritis. Various treatment strategies have been developed, including surgical techniques and cellular therapies, but they all show limitations. In this context, tissue engineering approaches, particularly 3D bioprinting, are promising for generating osteochondral tissue substitutes for joint repair. In this work, two biofabrication techniques, casting and extrusion-based 3D bioprinting, of an optimized formulation of a gelatin/alginate/fibrinogen bioink loaded with murine mesenchymal stromal cells (MSCs) were compared for the generation of cartilage and bone substitutes. Cell viability, proliferation and differentiation were characterized. Both techniques showed similar results in terms of viability and proliferation, but only the 3D bioprinted constructs allowed for differentiation towards the chondrogenic or osteogenic lineage using specific culture media. Bioprinting of biphasic osteochondral constructs comprising a cartilage compartment on top of a bone compartment was also explored. The study highlights the potential of our natural composite hydrogel bioink and extrusion-based 3D bioprinting for the generation of osteochondral tissue substitutes. Although further optimizations are needed, the study laid the groundwork for future advancements in osteochondral tissue engineering.

N-(4-methoxyphenyl) quinoline-8-sulfonamide reduces the inflammatory response of fibroblast-like synoviocytes by targeting receptor (calcitonin) activity modifying protein 1 in rheumatoid arthritis

BackgroundRheumatoid arthritis (RA) is characterized by chronic inflammation of the synovium of joints. Fibroblast-like synoviocytes (FLS) play an important role in RA pathogenesis. We aimed to investigate the effect of N-(4-methoxyphenyl) quinoline-8-sulfonamide (QS-3g) on the inflammatory response of FLS and explore the potential underlying mechanisms. MethodsWe screened and found that QS-3g exhibits the best anti-inflammatory response against FLS using the CCK8 assay. To investigate the therapeutic effects of QS-3g on K/BxN STA mice, we used H&E staining, immunofluorescence, immunohistochemistry, micro-CT, and other techniques. Additional investigations, including RNA-seq, molecular docking, and CETSA, revealed that QS-3g binds to RAMP1. ResultsAmong a series of 8-quinoline sulfonyl amide derivatives, QS-3g reduced the inflammatory response in TNF-α stimulated FLS, such as the release of interleukin (IL)-1β and IL-6. H&E staining and micro-CT showed that QS-3g inhibited synovial hypertrophy, inflammatory cell infiltration, and bone destruction. RNA-seq and CETSA analyses revealed the targeted inhibition of RAMP1 by QS-3g. Inhibition of RAMP1 expression could reduce IL-6 and IL-1β levels. Compared with RAMP1-si, combined administration of QS-3g and RAMP1-si reduced the TNF-α-induced inflammation in TNF-α stimulated FLS without statistically significant differences. Finally, the results of in vitro experiments showed that QS-3g could restore the balance of Gαi/Gαs by inhibiting Gαi and activating Gαs and up-regulate the expression of cAMP protein, thus inhibiting the RAMP1-mediated inflammatory response in FLS. ConclusionQS-3g could inhibit RAMP1 activity and mediate the Gαs/Gαi–cAMP pathway to reduce FLS inflammatory response. Therefore, QS-3g may serve as a novel anti-inflammatory compound for treating RA.

Villo-Nodular Synovitis of the Knee: A Case Report and Review of the Literature

Villonodular synovitis (VNS) is a benign tumor of the joint synovium, tendon sheaths and bursae. It is a rare condition of unknown pathogenesis [1], occurring preferentially in the knees. There are localized, diffuse and mixed forms [2]. Although the clinical manifestations are aspecific, MRI allows a diagnostic approach, even if it can have differential diagnostic problems in case of atypia or with synovial sarcoma. Treatment consists of complete removal of the lesion to avoid recurrence [3].

Treatment Modalities for Refractory-Recurrent Tenosynovial Giant Cell Tumor (TGCT): An Update

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.

Osteoarthritis early-, mid- and late-stage progression in the rat medial meniscus transection model.

Osteoarthritis is a degenerative disease of synovial joints affecting all tissues, including articular cartilage and subchondral bone. Osteoarthritis animal models can recapitulate aspects of human disease progression and are used to test efficacy of drugs, biomaterials, and cell therapies. The rat medial meniscus transection (MMT) model is a surgically induced posttraumatic osteoarthritis model commonly used for preclinical therapeutic screening. We describe herein, the qualitative and quantitative changes to articular cartilage, subchondral bone, and formation of osteophytes at early-, mid-, and late-stages of osteoarthritis progression. Tibia of MMT-operated animals showed proteoglycan loss and fibrillation along articular cartilage surfaces as early as 3-weeks post-surgery. With contrast-enhanced micro-CT technique, quantitative, 3-dimensional analysis of the tibia showed that the articular cartilage thickened at 3- and 6-weeks post-surgery and decreased at 12-weeks post-surgery. This decreased cartilage thickness corresponded with increased lesions in the articular cartilage that led to its full degradation and exposing the subchondral bone layer. Further, subchondral bone thickening was significant at 6-weeks post-surgery and followed cartilage damage. Osteophytes were found as early as 3-weeks post-surgery and coincided with articular cartilage degradation. Cartilaginous osteophytes preceded mineralization, suggesting endochondral ossification. The rat MMT model has predominantly been used out to 3-weeks, and most studies determined the effect of therapies to delay or prevent the onset of osteoarthritis. We provide evidence that an extension of the rat MMT model out to 6- and 12-weeks more resembled severe phenotypes of human osteoarthritis. Thus, evaluating novel therapeutics at late-stage will be important for eventual clinical translation.

Prodrug Nanomedicine for Synovium Targeted Therapy of Inflammatory Arthritis: Insights from Animal Model and Human Synovial Joint Fluid.

Many patients cannot tolerate low-dose weekly methotrexate (MTX) therapy for inflammatory arthritis treatment due to life-threatening toxicity. Although biologics offer a target-specific therapy, it raises the risk of serious infections and even cancer due to immune system suppression. We introduce an anti-inflammatory arthritis MTX ester prodrug using a long-circulating biocompatible polymeric macromolecule: folic acid (FA) functionalized hyperbranched polyglycerol (HPG). In vitro the drug MTX is incrementally released through pH and enzymatic degradation over 2 weeks. The role of matrix metalloproteinases (MMPs) in site-specific prodrug activation was verified using synovial fluid (SF) of 26 rheumatology patients and 4 healthy controls. Elevated levels of specific MMPs-markers of joint inflammation-positively correlated with enhanced prodrug release explained by acid-catalyzed hydrolysis of esters by proteases. Intravenously administered 111In-radiolabeled prodrug confirmed by SPECT/CT imaging that it accumulated preferentially in inflamed joints while reducing off-target side-effects in a mouse model of rheumatoid arthritis (RA). Added FA as a targeting vector prolonged prodrug action; prodrug with 4x less MTX applied every 2 weeks was as effective as weekly MTX therapy. The preclinical results suggest a prodrug-based strategy for the treatment of inflammatory joint diseases, with potential for other chronic inflammatory diseases and cancer.

Impact of Hatha and Iyengar Yoga on Physical Function and Quality of Life in Knee Osteoarthritis: A Systematic Review

Background: Osteoarthritis (OA) is a chronic degenerative disorder that primarily affects the articular cartilage of synovial joints. This condition leads to pain, joint stiffness, decreased muscle performance, and decreased aerobic capacity, which can negatively impact a patient's quality of life (QOL) and increase their risk of disability. This systematic review aims to investigate the effectiveness of two non-pharmacological treatment regimens, Hatha yoga, and Iyengar yoga, on QOL, physical function, and mental health in patients with knee OA. Methods: This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A comprehensive search was performed across three electronic databases: PubMed, Google Scholar, and ScienceDirect, to identify eligible studies that examined the beneficial effects of Hatha Yoga and Iyengar Yoga on improving physical function, mental health, and QOL in patients with knee OA. Results: Out of 61 reports initially identified, 51 were excluded based on the pre-defined inclusion and exclusion criteria. The results of this systematic review suggest that the combination of Hatha Yoga and Iyengar Yoga can enhance physical function, mental health, and QOL in patients with knee OA. Conclusion: Both Hatha Yoga and Iyengar Yoga can serve as effective complementary treatments alongside conventional treatment to improve the overall well-being of individuals with knee OA.

Diagnostic Accuracy of Pre-operative Percutaneous Synovial Biopsy and Aspirate Compared with Open Biopsy for Prosthetic Shoulder Infections

BackgroundShoulder arthroplasty revision is associated with a high prevalence of prosthetic infection, and diagnosis remains difficult. The primary aim of the study was to determine the diagnostic accuracy of percutaneous synovial biopsy (PSB) and joint aspiration compared with open culture results in detecting infection in revision shoulder arthroplasty. The second aim was to determine whether biopsy location within the shoulder was associated with culture status. MethodsThis was a multicenter prospective cohort study involving four sites and 69 patients undergoing revision shoulder arthroplasty. The cohort was 57% female with a mean age of 64 years. Preoperative fluoroscopic-guided PSB’s and aspirates were carried out by a musculoskeletal radiologist prior to revision shoulder arthroplasty. The original prostheses consisted of hemiarthroplasties, total shoulder arthroplasties (TSA), resurfacing TSA, reverse shoulder arthroplasties (RSA), and antibiotic spacers. Six synovial tissue biopsies from separate regions in the shoulder were obtained both preoperatively and intra-operatively. The shoulder joint was aspirated, and synovial fluid collected, if available. Infection was considered positive in the setting of two or more matching positive cultures. The PSB cultures were considered “true positive” if the PSB cultures matched the open biopsy cultures. ResultsNineteen percent had positive infection based on PSB and 23% had confirmed culture positive infections based on intra-operative biopsy. The diagnostic accuracy of PSB compared with open biopsy was as follows: sensitivity 0.37 (95% CI 0.13-0.61), specificity 0.81 (95% CI 0.7-0.91), positive predictive value 0.37 (95% CI 0.13 – 0.61), negative predictive value 0.81 (95% CI 0.70-0.91), positive likelihood ratio 1.98 and negative likelihood ratio 0.77. Of the 71 patients, aspiration yielded synovial fluid in 33 patients. Preoperative aspirates detected no infections confirmed positive by open biopsy and correctly identified 81% of absent infections. The diagnostic accuracy of aspirates compared with open biopsy was as follows: sensitivity 0%, specificity 0.81 (95% CI 0.66-0.96), positive predictive value 0%, negative predictive value 0.78 (95% CI 0.63-0.93). Biopsy location within the shoulder was not associated with infection status. DiscussionPreoperative aspiration detected none of the infections proven positive via open biopsy. Although PSB was superior to synovial fluid aspirate, poor likelihood ratios suggests that PSB is not useful as an isolated test in the preoperative workup of the potentially infected patient.Biopsy location was not associated with culture status suggesting that the capsule is uniformly infected, and the location of tissue biopsies does not appear to matter.