Animal Models Of Osteoarthritis Research Articles

IS IL-1 still the “OA cytokine”

Interleukin-1 has long been considered critical in the pathogenesis of osteoarthritis (OA) because of its roles in degrading cartilage, driving inflammation, and even in upregulating nerve growth factor. Given the growth of targeted biologic therapies in the last 20 years, interleukin-1 inhibition seemed a likely critical target. However, OA animal models have provided discrepant results on anti-IL-1 therapies, perhaps in part reflecting not only different animal models but prophylactic versus therapeutic experiments.

Machine learning based prioritisation of osteoarthritis joint damage associated genes using skeletal genetics and genomics

Purpose: Animal models are widely used in the study of osteoarthritis to investigate the effect of genetic or transient gene modulation on joint damage phenotypes. We recently described a knowledge base of gene modulations in osteoarthritis animal models, OATargets, that details the effect of 485 uniquely modulated genes (“OA genes”) in 661 publications published over the last 20 years. We continue to update and add new data types to this knowledge base to aid prioritisation of future laboratory investigation and suggest drug potential targets for osteoarthritis.

Photobiomodulation Therapy (Light-Emitting Diode 630 nm) Favored the Oxidative Stress and the Preservation of Articular Cartilage in an Induced Knee Osteoarthritis Model.

Objective: To evaluate the effects of photobiomodulation (PBM) therapy on oxidative stress and histological aspects of knee osteoarthritis (OA) induced by sodium monoiodoacetate in Wistar rats. Background: OA is a chronic degenerative disease. In addition to the inflammatory role, other factors, such as redox balance, appear to contribute to changes in the articular cartilage, the main articular structure affected. PBM therapy using light-emitting diode (LED) has been proposed to treat the disease by favoring anti-inflammatory effects and modulating markers of oxidative stress, acting on the degenerative process of cartilage. Methods: Twenty-seven male rats were separated into three groups: control (CG), OA (OAG), and LED treatment (LEDG). In the LED group, PBM (LED 630 nm, 300 mW, 9 J/cm2, 0.3 W/cm2, 30 sec) was applied, starting 24 h after induction, three times per week, for 8 weeks. Cartilage thickness, number of chondrocytes, enzymatic antioxidant defenses [superoxide dismutase (SOD) and catalase (CAT)], oxidative damage [thiobarbituric acid reactive substances (TBARS)], and nonenzymatic defense (ferric reducing antioxidant power) were analyzed. Results: The LEDG had higher average cartilage thickness compared with the OAG and had similar thickness to the CG. Also, the number of chondrocytes was similar to the CG. In the oxidative stress analysis, the LEDG presented antioxidant enzymatic activity (SOD and CAT) higher than the CG, and presented concentration of TBARS lower than the CG and OAG groups. Conclusions: PBM therapy was effective in recovering oxidative stress and preserving the articular cartilage aspects in a knee OA animal model.

TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis

Osteoarthritis (OA) is the most prevalent age-related disorder due to cartilage degradation. Previous studies have identified aberrant chondrocyte homeostasis under extracellular stress as a key pathological mechanism behind cartilage degradation in OA. TDP-43, a DNA/RNA-binding protein has been demonstrated to participate in processing many extracellular stress responses; however, understanding of the role of TDP-43 in OA is limited. This study aims to investigate the role of TDP-43 in chondrocyte homeostasis and cartilage degradation in OA. The role of TDP-43 during degradation of cartilage is examined by experimental posttraumatic OA animal models and human cartilage specimens. Cartilage degradation is assessed by histological analysis, qPCR, and Western blot. The molecular mechanisms are investigated in vitro using human primary chondrocytes. TDP-43 decreases significantly in degenerated cartilage. TDP-43 concentration is positively correlated with IL-1β concentration in synovial fluid derived from OA patients (Pearson r=0.95, CI (95%) [0.80, 0.99], P<0.0001). Intra-articular injection of recombinant TDP-43 significantly alleviates cartilage degradation and subchondral bone remodeling in vivo. In vitro mechanistic analyses show that TDP-43 maintains chondrocyte homeostasis under oxidative stress through regulating stress granule dynamics via G3BP1. The present study indicates that TDP-43 maintains chondrocyte homeostasis under oxidative stress and alleviates cartilage degeneration in osteoarthritis, identifying TDP-43 as a potential target for the diagnosis and treatment of knee OA.

LINC02288 promotes chondrocyte apoptosis and inflammation through miR-374a-3p targeting RTN3.

Dysregulation of long non-coding RNAs (lncRNAs) is related to the occurrence of osteoarthritis (OA). In the present study, we explored the role of LINC02288 and its regulatory mechanism in OA development. GSE113825 was obtained from Gene Expression Omnibus (GEO) database and analyzed to identify the differentially expressed lncRNAs in OA. Gene enrichment analyses and Kyoto Encyclopedia of Genes and Genomes biological process analysis were performed through Metascape (http://metascape.org/gp). The interactions among LINC02288, miR-374a-3p and RTN3 were determined using RNA immunoprecipitation (RIP) assays and dual luciferase reporter assays. Chondrocyte apoptosis was examined using flow cytometry. Western blot assays were conducted to assess the pro-apoptotic and anti-apoptotic markers. We identified a total of 4,491 differentially expressed lncRNAs. We focused on LINC02288 as the top-ranked up-regulated lncRNA in OA as indicated by a significant p-value. LINC02288 was significantly up-regulated, which was further verified by a real-time polymerase chain reaction. Down-regulation of LINC02288 significantly reduced the apoptosis of OA chondrocytes induced by interleukin-1β and the production of pro-inflammatory cytokines. These effects were further verified in an OA rat model. An RIP assay and dual luciferase assay further confirmed that LINC02288 served as a sponge of miR-374a-3p. Moreover, the overexpression of RTN3 could partially reverse the effects of LINC02288 knockdown, mediating inhibitory effects on chondrocyte apoptosis and the inflammatory response. Down-regulation of LINC02288 alleviated OA development in an in vivo OA animal model. Our findings indicate that LINC02288 contributes to OA progression by targeting the miR-374a-3p/RTN3 axis, which might provide a promising molecular therapy strategy for OA.

Secretome of human adipose-derived mesenchymal stem cell relieves pain and neuroinflammation independently of the route of administration in experimental osteoarthritis

ObjectiveTreatment of pain associated with osteoarthritis (OA) is unsatisfactory and innovative approaches are needed. The secretome from human adipose-derived mesenchymal stem cells (hASC-Conditioned Medium, CM) has been successfully used to relieve painful symptoms in models of chronic pain. The aim of this study was to explore the efficacy of the hASC-CM to control pain and neuroinflammation in an animal model of OA. MethodsOA was induced in mice by intra-articular monosodium-iodoacetate (MIA) injection. Thermal hyperalgesia and mechanical allodynia were assessed. Once hypersensitivity was established (7 days after MIA), hASC-CM was injected by IA, IPL and IV route and its effect monitored over time. Neuroinflammation in nerve, dorsal root ganglia and spinal cord was evaluated measuring proinflammatory markers and mediators by RT-qPCR. Protein content analysis of secretome by Mass Spectrometry was performed. ResultsA single injection with hASC-CM induced a fast and long lasting antihyperalgesic and antiallodynic effect. The IV route of administration appeared to be the most efficacious although all the treatments were effective. The effect on pain correlated with the ability of hASC-CM to reduce the neuroinflammatory condition in both the peripheral and central nervous system. Furthermore, the secretome analysis revealed 101 factors associated with immune regulation. ConclusionWe suggest that hASC-CM is a valid treatment option for controlling OA-related hypersensitivity, exerting a rapid and long lasting pain relief. The mechanisms underpinning its effects are likely linked to the positive modulation of neuroinflammation in peripheral and central nervous system that sustains peripheral and central sensitization.

The Rationale for the Intra-Articular Administration of Clodronate in Osteoarthritis.

Background: Several pharmacological therapeutic approaches have been proposed to manage osteoarthritis (OA), including intra-articular (IA) injections. Although the discovery of clodronate, a bisphosphonate, dates back to the 1960s and the effects of its IA administration have been investigated for decades in animal models, mechanisms of action of this drug are not quite clear, particularly in OA. This scoping review is an overview of the biological as well as the clinical role of clodronic acid in OA. Method: A scoping review based on the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) model was performed to characterize the mechanisms of action of IA clodronate in OA and to evaluate its efficacy from a clinical point of view. Results: Several effects of clodronate have been observed in animal models of OA, including depletion of synovial lining cells that results in reduced production of chemokines (IL-1, TNF- α), growth factors (TGF-β, BMP 2/4), and metalloproteases (MMP 2/3/9); prevention of cartilage damage, synovial hyperplasia, and proteoglycans loss; reduction in joint inflammation, joint swelling, and osteophyte formation. From a clinical perspective, patients with knee OA treated with IA clodronate experienced improvements in pain and joint mobility. Conclusion: Clodronate appears to have different mechanisms of action interfering with the pathogenic processes contributing to OA development and progression. This intervention demonstrated positive effects for patients affected by knee OA.

Quantitative measures of bone shape, cartilage morphometry and joint alignment are associated with disease in an ACLT and MMx rat model of osteoarthritis.

Multi-scale, subject-specific quantitative methods to characterize and monitor osteoarthritis in animal models and therapeutic treatments could help reveal causal relationships in disease development and distinguish treatment strategies. In this work, we demonstrate a reproducible and sensitive quantitative image analysis to characterize bone, cartilage and joint measures describing a rat model of post-traumatic osteoarthritis. Eleven 3-month-old male Wistar rats underwent medial anterior cruciate ligament (ACL) transection and medial meniscectomy on the right knee to destabilise the right tibiofemoral joint. They were sacrificed 6weeks post-surgery and a silicon-based micro-bead contrast agent was injected in the joint space, before scanning with micro-computed tomography (microCT). Subsequently, 3D quantitative morphometric analysis (QMA), previously developed for rabbit joints, was performed. This included cartilage, subchondral cortical and epiphyseal bone measures, as well as novel tibiofemoral joint metrics. Semi-quantitative evaluation was performed on matching two-dimensional (2D) histology and microCT images. Reproducibility of the QMA was tested on eleven age-matched additional joints. The results indicate the QMA method is accurate and reproducible and that microCT-derived cartilage measurements are valid for the analysis of rat joints. The pathologic changes caused by transection of the ACL and medial meniscectomy were reflected in measurements of bone shape, cartilage morphology, and joint alignment. Furthermore, we were able to identify model-specific predictive parameters based on morphometric parameters measured with the QMA.

Endoglin Level Is Critical for Cartilage Tissue Formation In Vitro by Passaged Human Chondrocytes.

Transforming growth factor beta (TGFβ) signaling is required for in vitro chondrogenesis. In animal models of osteoarthritis (OA), TGFβ receptor alterations are detected in chondrocytes in severe OA cartilage. It is not known whether such changes are dependent on the grade of human OA and if they affect chondrogenesis. Thus, the purpose of this study was to determine if human OA chondrocytes obtained from low-grade or high-grade disease could form cartilage tissue and to assess the role of the co-receptors, endoglin (ENG) and TGFβ receptor 3 (TGFBRIII), in the regulation of this tissue generation in vitro. We hypothesized that the grade of OA disease would not affect the ability of cells to form cartilage tissue and that the TGFβ co-receptor, ENG, would be critical to regulating tissue formation. Chondrocytes isolated from low-grade OA or high-grade OA human articular cartilage (AC) were analyzed directly (P0) or passaged in monolayer to P2. Expression of the primary TGFβ receptor ALK5, and the co-receptors ENG and TGFβRIII, was assessed by image flow cytometry. To assess the ability to form cartilaginous tissue, cells were placed in three-dimensional culture at high density and cultured in chondrogenic media containing TGFβ3. ENG knockdown was used to determine its role in regulating tissue formation. Overall, grade-specific differences in expression of ALK5, ENG, and TGFβRIII in primary or passaged chondrocytes were not detected; however, ENG expression increased significantly after passaging. Despite the presence of ALK5, P0 cells did not form cartilaginous tissue. In contrast, P2 cells derived from low-grade and high-grade OA AC formed hyaline-like cartilaginous tissues of similar quality. Knockdown of ENG in P2 cells inhibited cartilaginous tissue formation compared to controls indicating that the level of ENG protein expression is critical for in vitro chondrogenesis by passaged articular chondrocytes. This study demonstrates that it is not the grade of OA, but the levels of ENG in the presence of ALK5 that influences the ability of human passaged articular chondrocytes to form cartilaginous tissue in vitro in 3D culture. This has implications for cartilage repair therapies. Impact statement These findings are important clinically, given the limited availability of osteoarthritis (OA) cartilage tissue. Being able to use cells from all grades of OA will increase our ability to obtain sufficient cells for cartilage repair. In addition, it is possible that endoglin (ENG) levels, in the presence of ALK5 expression, may be suitable to use as biomarkers to identify cells able to produce cartilage.

Chondrogenesis of human amniotic fluid stem cells in Chitosan-Xanthan scaffold for cartilage tissue engineering

Articular chondral lesions, caused either by trauma or chronic cartilage diseases such as osteoarthritis, present very low ability to self-regenerate. Thus, their current management is basically symptomatic, progressing very often to invasive procedures or even arthroplasties. The use of amniotic fluid stem cells (AFSCs), due to their multipotentiality and plasticity, associated with scaffolds, is a promising alternative for the reconstruction of articular cartilage. Therefore, this study aimed to investigate the chondrogenic potential of AFSCs in a micromass system (high-density cell culture) under insulin-like growth factor 1 (IGF-1) stimuli, as well as to look at their potential to differentiate directly when cultured in a porous chitosan-xanthan (CX) scaffold. The experiments were performed with a CD117 positive cell population, with expression of markers (CD117, SSEA-4, Oct-4 and NANOG), selected from AFSCs, after immunomagnetic separation. The cells were cultured in both a micromass system and directly in the scaffold, in the presence of IGF-1. Differentiation to chondrocytes was confirmed by histology and by using immunohistochemistry. The construct cell-scaffold was also analyzed by scanning electron microscopy (SEM). The results demonstrated the chondrogenic potential of AFSCs cultivated directly in CX scaffolds and also in the micromass system. Such findings support and stimulate future studies using these constructs in osteoarthritic animal models.

Topographical and zonal patterns of T2 relaxation in osteoarthritic tibial cartilage by low- and high-resolution MRI

PurposeThis study aimed to establish the topographical and zonal T2 patterns of multi-resolution MRI in medial tibial cartilage in a canine model of osteoarthritis (OA), initiated by the anterior cruciate ligament (ACL) transection surgery, and studied after 8-weeks and 12-weeks post-surgery. MethodsArticular cartilage from healthy, two stages of contralateral, and of OA knees were quantitatively imaged by the MRI T2 protocols at two imaging resolutions (100 and 17.6 μm/pixel). The zonal T2 changes at five topographical locations (anterior (AMT), exterior (EMT), posterior (PMT), central (CMT) and interior (IMT) medial tibia) and subsequent two averaged regions (covered by meniscus and exposed) were analyzed. At each location, full-thickness cartilage was studied in four sub-tissue zones (superficial, transitional, upper and lower radial zones). ResultsTissue degradation can be detected by measurable changes of T2, which is resolution- and orientation-dependent. T2 changes ranging from +28.82% increase (SZ, PMT) to −23.15% decrease (RZ1, AMT) in healthy to disease (8C), with the largest increase of T2 in the surface tissue. Various location-dependent patterns of degradation are found over the tibial surface, most commonly shown in early-stage OA (8C) on the anterior site, different from the posterior. Finally, the contralateral cartilage has specific degradation patterns, different from those in OA cartilage. ConclusionsThis is the first quantitative and highest multi-resolution characterization of cartilage at five topographical locations over the medial tibial plateau with fine zonal resolution in an animal model of OA, which would benefit future investigation of human OA in clinics.

Mesenchymal Stem Cell Therapy for Osteoarthritis: Practice and Possible Promises.

Osteoarthritis (OA) is a common progressively degenerative joint disease that affects more than 300million people worldwide. OA is manifested by articular cartilage degradation, chronic pain, deformity, functional disability, and decreased quality of life. A real challenge in OA management is the lack of an effective cure because exiting therapeutics often provide symptom control rather than disease modification; therefore, they fail to prevent disease progression. The inadequate treatments for OA management have encouraged researchers to study mesenchymal stem cells (MSCs) as an investigational treatment for OA. MSCs are a promising tool for OA because of their availability; expand cultivation and multi-lineage differentiation capacity as well as well-documented paracrine function have made MSCs a promising tool in this field. Accordingly, MSCs application has been successfully utilized in a broad range of pre-clinical OA animal models as well as clinical studies with the aim of cartilage repair which had not previously been achieved using classical treatments. Here, the brief scientific review of MSC role in the control of OA as well as the proposed mechanisms are discussed. We provide an insight into the last 10years' studies conducted on preclinical and clinical OA treatment as well as future opportunities in OA management strategies employing MSCs.

Rejuvenated ageing mesenchymal stem cells by stepwise preconditioning ameliorates surgery-induced osteoarthritis in rabbits

AimsAgeing-related incompetence becomes a major hurdle for the clinical translation of adult stem cells in the treatment of osteoarthritis (OA). This study aims to investigate the effect of stepwise preconditioning on cellular behaviours in human mesenchymal stem cells (hMSCs) from ageing patients, and to verify their therapeutic effect in an OA animal model.MethodsMesenchymal stem cells (MSCs) were isolated from ageing patients and preconditioned with chondrogenic differentiation medium, followed by normal growth medium. Cellular assays including Bromodeoxyuridine / 5-bromo-2'-deoxyuridine (BrdU), quantitative polymerase chain reaction (q-PCR), β-Gal, Rosette forming, and histological staining were compared in the manipulated human mesenchymal stem cells (hM-MSCs) and their controls. The anterior cruciate ligament transection (ACLT) rabbit models were locally injected with two millions, four millions, or eight millions of hM-MSCs or phosphate-buffered saline (PBS). Osteoarthritis Research Society International (OARSI) scoring was performed to measure the pathological changes in the affected joints after staining. Micro-CT analysis was conducted to determine the microstructural changes in subchondral bone.ResultsStepwise preconditioning approach significantly enhanced the proliferation and chondrogenic potential of ageing hMSCs at early passage. Interestingly, remarkably lower immunogenicity and senescence was also found in hM-MSCs. Data from animal studies showed cartilage damage was retarded and subchondral bone remodelling was prevented by the treatment of preconditioned MSCs. The therapeutic effect depended on the number of cells applied to animals, with the best effect observed when treated with eight millions of hM-MSCs.ConclusionThis study demonstrated a reliable and feasible stepwise preconditioning strategy to improve the safety and efficacy of ageing MSCs for the prevention of OA development.Cite this article: Bone Joint Res 2021;10(1):10–21.

Chitosan and Lecithin Ameliorate Osteoarthritis Symptoms Induced by Monoiodoacetate in a Rat Model.

The present work aimed to assess the chondroprotective influence of chitosan and lecithin in a monoiodoacetate (MIA)-induced experimental osteoarthritis (OA) model. Forty male rats weighing 180–200 g were randomly distributed among the following five experimental groups (eight per group): control, MIA-induced OA, MIA-induced OA + chitosan, MIA-induced OA + lecithin, and MIA-induced OA + chitosan + lecithin. The levels of TNF-α, IL6, RF, ROS, and CRP, as well as mitochondrial markers such as mitochondrial swelling, cytochrome C oxidase (complex IV), MMP, and serum oxidative/antioxidant status (MDA level) (MPO and XO activities) were elevated in MIA-induced OA. Also, SDH (complex II) activity in addition to the levels of ATP, glutathione (GSH), and thiol was markedly diminished in the MIA-induced OA group compared to in control rats. These findings show that mitochondrial function is associated with OA pathophysiology and suggest that chitosan and lecithin could be promising potential ameliorative agents in OA animal models. Lecithin was more effective than chitosan in ameliorating all of the abovementioned parameters.

A review of applications of metabolomics in osteoarthritis.

Osteoarthritis (OA) represents the most prevalent and disabling arthritis worldwide due to its heterogeneous and progressive articular degradation. However, effective and timely diagnosis and fundamental treatment for this disorder are lacking. Metabolomics, a growing field in life science research in recent years, has the potential to detect many metabolites and thus explains the underlying pathophysiological processes. Hence, new specific metabolic markers and related metabolic pathways can be identified for OA. In this review, we aimed to provide an overview of studies related to the metabolomics of OA in animal models and humans to describe the metabolic changes and related pathways for OA. The present metabolomics studies reveal that the pathogenesis of OA may be significantly related to perturbations of amino acid metabolism. These altered amino acids (e.g., branched-chain amino acids, arginine, and alanine), as well as phospholipids, were identified as potential biomarkers to distinguish patients with OA from healthy individuals.

Combinatmarion treatment with Lactobacillus acidophilus LA-1, vitamin B, and curcumin ameliorates the progression of osteoarthritis by inhibiting the pro-inflammatory mediators

Disease-modifying osteoarthritis (OA) therapy is not yet available. Several adjuvant therapies have demonstrated promising results in the treatment of OA. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a combination of Lactobacillus acidophilus, vitamin B, and curcumin in the treatment of OA.Monosodium iodoacetate (MIA)-induced arthritis of the knee joint in rat was used as an animal model of human OA. The combination of L. acidophilus LA-1, vitamin B, and curcumin or a saline solution was given orally. Pain was measured according to the paw withdrawal latency, and paw withdrawal threshold.Cartilage destruction was analyzed using histomorphological techniques and the Mankin scoring system. Protein expression in the joint was examined using immunohistochemistry. The effects of the combination of L. acidophilus LA-1, vitamin B, and curcumin on mRNA levels in chondrocytes stimulated with interleukin (IL)-1β were analyzed using real-time polymerase chain reaction.The combination of L. acidophilus, vitamin B, and curcumin effectively downregulated Th17 cells and the related cytokine IL-17, thereby maintained the Treg population, and increased the expression of the Treg-related cytokine IL-10 in human peripheral blood mononuclear cells. The OA animal model exhibited reduced pain and preservation of cartilage in response to the combination treatment. The expression levels of pro-inflammatory cytokines and the catabolic, matrix metalloproteinase-13 (MMP-13), were decreased, whereas the expression of the anabolic tissue inhibitors of metalloproteinases (TIMPs) were upregulated in response to the drug combination.The combination of L. acidophilus, vitamin B, and curcumin was beneficial in OA treatment, controlling the inflammatory response via regulation of the Th17/Treg population and reducing the expression of pro-inflammatory cytokines in human peripheral blood mononuclear cells. The combination treatment also preserved cartilage, suppressed osteoclastogenesis, and regulated the anabolic/catabolic imbalance. These findings indicate the therapeutic potential of combination use of L. acidophilus, vitamin B, and curcumin in patients with OA.

OATargets: a knowledge base of genes associated with osteoarthritis joint damage in animals

ObjectivesTo collate the genes experimentally modulated in animal models of osteoarthritis (OA) and compare these data with OA transcriptomics data to identify potential therapeutic targets.MethodsPubMed searches were conducted to identify...

Alterations in Anandamide Synthesis and Degradation during Osteoarthritis Progression in an Animal Model.

Osteoarthritis (OA) is a degenerative joint disease manifested by movement limitations and chronic pain. Endocannabinoid system (ECS) may modulate nociception via cannabinoid and TRPV1 receptors. The purpose of our study was to examine alterations in the spinal and joint endocannabinoid system during pain development in an animal model of OA. Wistar rats received intra-articular injection of 3mg of sodium monoiodoacetate (MIA) into the knee joint. Animals were sacrificed on day 2, 7, 14, 21, 28 after injection and lumbar spinal cord, cartilage and synovium were collected. Changes in the transcription levels of the ECS elements were measured. At the spinal level, gene expression levels of the cannabinoid and TRPV1 receptors as well as enzymes involved in anandamide synthesis and degradation were elevated in the advanced OA phase. In the joint, an important role of the synovium was demonstrated, since cartilage degeneration resulted in attenuation of the changes in the gene expression. Enzymes responsible for anandamide synthesis and degradation were upregulated particularly in the early stages of OA, presumably in response to early local joint inflammation. The presented study provides missing information about the MIA-induced OA model and encourages the development of a therapy focused on the molecular role of ECS.

Reduction in Osteoarthritis Risk After Treatment With Ticagrelor Compared to Clopidogrel: A Propensity Score-Matching Analysis.

Osteoarthritis (OA) is a common cause of joint pain and disability, and effective treatments are lacking. Extracellular adenosine has antiinflammatory effects and can prevent and treat OA in animal models. Ticagrelor and clopidogrel are both used in patients with coronary artery disease, but only ticagrelor increases extracellular adenosine levels. This study was undertaken to determine whether treatment with ticagrelor was associated with a lower risk of OA. We conducted a 1:2 propensity score-matching analysis using data from 2011-2017 in the Optum Clinformatics Data Mart. Patients who had received either ticagrelor or clopidogrel for ≥90 days were included in our study, and patients with a prior diagnosis of OA or inflammatory arthritis were excluded. OA was identified using International Classification of Diseases codes. The primary outcome was the time to diagnosis of OA after treatment with ticagrelor versus clopidogrel. Our propensity score-matched cohort consisted of 7,007 ticagrelor-treated patients and 14,014 clopidogrel-treated patients, with a median number of days receiving treatment of 287 and 284, respectively. For both groups, the mean age was 64 years, and 73% of the patients were male. Multivariate Cox regression analysis estimated a hazard ratio for developing OA of 0.71 (95% confidence interval 0.64-0.79) (P < 0.001) after treatment with ticagrelor compared to clopidogrel. Treatment with ticagrelor was associated with a 29% lower risk of developing OA compared to treatment with clopidogrel over 5 years of follow-up. We hypothesize that the reduction in OA seen in patients who received ticagrelor may in part be due to increased extracellular adenosine levels.

Synthesis of N,N′-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide that ameliorate osteoarthritis symptoms and improve bone marrow matrix structure and cartilage alterations induced by monoiodoacetate in the rat model: “Suggested potent anti-inflammatory agent against COVID-19”

To assess the chondroprotective effect and influence of N,N′-bis(1,5-dimethyl-2-phenyl-1,2-dihydro-3-oxopyrazol-4-yl) sebacamide (dpdo) that was synthesized through the reaction of phenazone with sebacoyl chloride and screened for its biological activity especially as anti-arthritic and anti-inflammatory agent in a monoiodoacetate (MA)-induced experimental osteoarthritis (OA) model. Thirty male albino rats weighing “190–200 g” were divided randomly into three groups (10 each): control, MA-induced OA, and MA-induced OA + dpdo. In MA-induced OA rat, the tumor necrosis factor alpha, interleukin 6, C-reactive protein, rheumatoid factors, reactive oxygen species, as well as all the mitochondrial markers such as mitochondria membrane potential, swelling mitochondria, cytochrome c oxidase (complex IV), and serum oxidative/antioxidant status (malondialdehyde level and activities of myeloperoxidase and xanthine oxidase) are elevated. Also, the activity of succinate dehydrogenase (complex II), levels of ATP, the level of glutathione (GSH), and thiol were markedly diminished in the MA-induced OA group compared to the normal control rats. These findings showed that mitochondrial function is associated with OA pathophysiological alterations and high gene expressions of (IL-6, TNF-a, and IL-1b) and suggests a promising use of dpdo as potential ameliorative agents in the animal model of OA and could act as anti-inflammatory agent in case of severe infection with COVID-19. It is clearly appeared in improving the bone cortex and bone marrow in the treated group with the novel compound in histological and transmission electron microscopic sections which is a very important issue today in fighting severe infections that have significant effects on the blood indices and declining of blood corpuscles like COVID-19, in addition to declining the genotoxicity and inflammation induced by MA in male rats. The novel synthesized compound was highly effective in improving all the above mentioned parameters.