Treatment Of OA Research Articles

Classifying Pre-Radiographic Osteoarthritis of the Knee Using Wearable Acoustics Sensing at the Point of Care.

This study was undertaken to determine if knee acoustic emissions (KAE) measured at the point of care with a wearable device can classify knees with pre-radiographic osteoarthritis (pre-OA) from healthy knees. We performed a single-center cross-sectional observational study comparing KAE in healthy knees to knees with clinical symptoms compatible with knee OA that did not meet classification criteria for radiographic knee OA. KAE were measured during scripted maneuvers performed in clinic exam rooms or similarly noisy medical center locations in healthy (n=20), pre-OA (n=11), and, for comparison, OA (n=12) knees. Acoustic features were extracted from the KAE and used to train models to classify pre-OA, OA, and control knees with logistic regression. Model performance was measured and optimized with Leave-One-Out Cross-Validation. Regressive sensitivity analysis was performed to combine acoustic information from individual maneuvers to further optimize performance. Test-retest reliability of KAE was measured with intraclass correlation analysis. Classification models trained with KAE were accurate for both pre-OA and OA (94% accurate, 0.96 and 0.99 area under a receiver operating characteristic curve (AUC), respectively). Acoustic features selected for use in the optimized models had high test-retest reliability by intrasession and intersession intraclass correlation analysis (mean intraclass correlation coefficient 0.971 +/- 0.08 standard deviation). Analysis of KAE measured in acoustically uncontrolled medical settings using an easily accessible wearable device accurately classified pre-OA knees from healthy control knees in our small cohort. Accessible methods of identifying pre-OA could enable regular joint health monitoring and improve OA treatment and rehabilitation outcomes.

Anti-osteoarthritis effects of injectable hyaluronic acid hydrogel loaded with platelet lysate and cerium oxide nanoparticle by regulating TNF-α: An in vitro model

The most prevalent type of joint illness is osteoarthritis, also known as OA. The inflammation of the joint is strongly linked to both the beginning and the progression of osteoarthritis. The use of hydrogels as an OA treatment has the potential to go beyond the administration of anti-inflammatory components to have an inherent immunomodulatory role. Platelet lysate (PL) contains a cocktail of growth factors that actively participates in cartilage repair. Moreover, cerium oxide-nanoparticles (CeO2-NPs) have been broadly studied owing to their powerful antioxidant properties and potential preventive and therapeutic effects against chronic diseases. The current study was designed to determine the effect and mechanism of injectable hyaluronic acid (HA) hydrogel loaded with PL and CeO2-NPs on OA. The results showed that the obtained PL and synthesized CeO2-NPs were effectively incorporated into HA hydrogel and the resultant hydrogel was injectable and have a porous micro structure with interconnected pores. The biological evaluation by qPCR revealed that the fabricated hydrogel exhibited a significantly increased expression of Col2 and Aggrecan (TNF-α-suppressed anabolic molecules) and decreased expression of Col10, Mmp13, Adamts5, and Adamts9 (TNF-α-activated catabolic molecules). Also, ELISA results confirmed this potent antioxidant activity of hydrogel and also increased the growth of chondrocytes over the culturing period.

Recent advances in porous nanomaterials‐based drug delivery systems for osteoarthritis

AbstractOsteoarthritis (OA) is a common degenerative disease that develops over time, characterized mainly by inflammatory joints, cartilage deterioration, and ultimately loss of normal joint function. Some of the limitations that restrict the effectiveness of current OA treatment procedures include minimal penetration of medications into cartilage and lack of vascularity, leading to insufficient bioavailability and systemic toxicity. To increase the effectiveness of treatment, it is necessary to create novel non‐invasive OA treatment techniques. Porous nanomaterials (PNMs) show great promise as sustained drug delivery systems (DDSs) due to their functionality, variable porosity, and high loading capacity. In addition, they can provide targeted drug delivery, facilitate controlled release of drugs, and prolong drug circulation and retention time while reducing adverse reactions and improving drug solubility. First, the current treatment methods and challenges are summarized. Subsequently, recent advances in DDSs for OA treatment based on PNMs with various pore sizes and structures are presented. Lastly, the parameters that affect the performance of DDSs are discussed by giving some suggestions for their design. The purpose of this review is to provide new insights into PNM‐based DDS design and to inspire readers to adopt the smart design of intra‐articular DDSs in the future.

Upregulation of cIAP1 induced by AZD8330 alleviates osteoarthritis progression by inhibiting the RIP1-associated necrosis signaling pathway

BackgroundOsteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management. MethodsIn this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis. ResultsOur investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy. ConclusionsOur study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.

Role of hydrogels in osteoarthritis: A comprehensive review.

Osteoarthritis (OA) is a chronic, degenerative, and age-related disease. It is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. The current effective treatment for OA is limited. Hydrogel is a kind of unique carrier with well-known biocompatibility, softness, and high water content among various biomaterials. Hydrogels are developed for different biomedical applications, for instance, drug delivery, and tissue engineering. To date, a variety of hydrogels-based therapies have been used in OA patients or animal models. In this review, we comprehensively summarized the potential role of hydrogels in chondrocytes proliferation, apoptosis, and inflammatory component production and discussed the impact of hydrogels on OA development. The collection of this information will help better understand the present progress of hydrogels in OA.

The Dual Role of Small Extracellular Vesicles in Joint Osteoarthritis: Their Global and Non-Coding Regulatory RNA Molecule-Based Pathogenic and Therapeutic Effects.

OA is the most common joint disease that affects approximately 7% of the global population. Current treatment methods mainly relieve its symptoms with limited repairing effect on joint destructions, which ultimately contributes to the high morbidity rate of OA. Stem cell treatment is a potential regenerative medical therapy for joint repair in OA, but the uncertainty in differentiation direction and immunogenicity limits its clinical usage. Small extracellular vesicles (sEVs), the by-products secreted by stem cells, show similar efficacy levels but have safer regenerative repair effect without potential adverse outcomes, and have recently drawn attention from the broader research community. A series of research works and reviews have been performed in the last decade, providing references for the application of various exogenous therapeutic sEVs for treating OA. However, the clinical potential of target intervention involving endogenous pathogenic sEVs in the treatment of OA is still under-explored and under-discussed. In this review, and for the first time, we emphasize the dual role of sEVs in OA and explain the effects of sEVs on various joint tissues from both the pathogenic and therapeutic aspects. Our aim is to provide a reference for future research in the field.

Vector potential dual effect of promoting the proliferation of chondrocytes and inhibiting the calcification process in the articular cartilage

OA commonly affects the articular cartilage of the tibia, and its calcification worsens its advancement and its prevalence has recently increased. Vector potential (VP) represents a novel physical therapy for treating OA. Since the impact of VP on articular cartilage remains unknown, we aimed to assess its effects on articular cartilage and its potential as a new treatment for OA. Here, we divided 24 male Wistar rats, 6-week-old, into control (CO, n = 12) and VP stimulus (n = 12) groups (VP conditions: volt, 67 mV; frequency, 20 kHz; current, 0.12 mA; experimental frequency, 30 min/days, 5 days/week, and 3 weeks). Articular cartilage can be classified into four layers: superficial, medial, deep, and calcified. Moreover, the number of chondrocytes in the articular cartilage was higher in the CO group compared to the VP group, although the calcified layer was thinner in the VP group. Furthermore, MKi67 exhibited higher expression in the VP group than in the CO group, while ectonucleotide pyrophosphatase/phosphodiesterase 1 was downregulated in the VP group. Our findings indicate that VP positively influenced chondrocyte proliferation and inhibited calcification in articular cartilage. Thus, VP stimulation may assist in the development of novel strategies for preventing OA.

Piezo1 activation accelerates osteoarthritis progression and the targeted therapy effect of artemisinin

IntroductionOsteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide with no cure; its mechanism remains poorly defined. Abnormal mechanical stress is the main pathological factor of OA. ObjectivesTo investigate the effects of Piezo1 activation on OA development and progression and to explore Piezo1-targeting OA treatment. MethodsThe expression levels of Piezo1 were determined in human OA cartilage and experimental OA mice. Mice with genetic Piezo1 deletion in chondrocytes or intra-articular injection of the Piezo1 activator Yoda1 were utilized to determine the effects on DMM-induced OA progression. Effects of artemisinin (ART), a potent antimalarial drug, on Piezo1 activation, chondrocyte metabolism and OA lesions were determined. ResultsPiezo1 expression was elevated in articular chondrocytes in human OA and DMM-induced mouse OA cartilage. Piezo1 deletion in chondrocytes largely attenuates DMM-induced OA-like phenotypes. In contrast, intra-articular injection of Yoda1 aggravates the knee joint OA lesions in mice. PIEZO1 activation increases, while PIEZO1 siRNA knockdown decreases, expression of RUNX2 and catabolic enzymes MMP13 and ADAMTS5 in primary human articular chondrocytes in a PI3K-AKT dependent manner. We have provided strong evidence supporting that ART is a novel and potent inhibitor of Piezo1 activation in primary OA-HACs and all cell lines examined, including human endothelial HUVEC cells, ATDC5 chondrocyte-like cells and MLO-Y4 osteocytes-like cells. Results from in vitro experiments confirmed that ART decreases the Yoda1-induced increases in the levels of OA-related genes and p-PI3K and p-AKT proteins in OA-HACs and alleviates DMM-induced OA lesions in mice. ConclusionsWe establish a critical role of Piezo1 in promoting OA development and progression and define ART as a potential OA treatment.

(+)-Lipoic Acid Reduces Lipotoxicity and Regulates Mitochondrial Homeostasis and Energy Balance in an In Vitro Model of Liver Steatosis.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipids within hepatocytes, which compromises liver functionality following mitochondrial dysfunction and increased production of reactive oxygen species (ROS). Lipoic acid is one of the prosthetic groups of the pyruvate dehydrogenase complex also known for its ability to confer protection from oxidative damage because of its antioxidant properties. In this study, we aimed to investigate the effects of lipoic acid on lipotoxicity and mitochondrial dynamics in an in vitro model of liver steatosis. HepG2 cells were treated with palmitic acid and oleic acid (1:2) to induce steatosis, without and with 1 and 5 µM lipoic acid. Following treatments, cell proliferation and lipid droplets accumulation were evaluated. Mitochondrial functions were assessed through the evaluation of membrane potential, MitoTracker Red staining, expression of genes of the mitochondrial quality control, and analysis of energy metabolism by HPLC and Seahorse. We showed that lipoic acid treatment restored membrane potential to values comparable to control cells, as well as protected cells from mitochondrial fragmentation following PA:OA treatment. Furthermore, our data showed that lipoic acid was able to determine an increase in the expression of mitochondrial fusion genes and a decrease in mitochondrial fission genes, as well as to restore the bioenergetics of cells after treatment with palmitic acid and oleic acid. In conclusion, our data suggest that lipoic acid reduces lipotoxicity and improves mitochondrial functions in an in vitro model of steatosis, thus providing a potentially valuable pharmacological tool for NAFLD treatment.

Mir-25-3p in extracellular vesicles from fibroblast-like synoviocytes alleviates pyroptosis of chondrocytes in knee osteoarthritis.

Knee osteoarthritis (KOA) is defined as a joint disease that occurs mostly among elderly people. Fibroblast-like synoviocytes-derived extracellular vesicles (FLS-EVs) have impacts on the treatment of OA. This study elucidated the mechanism of miR-25-3p in pyroptosis of chondrocytes in KOA. FLSs and EVs were extracted from neonatal mice; destabilization of the medial meniscus (DMM) was used to simulate KOA in mice, followed by the evaluation of cartilage damage and the contents of MMP-3 and MMP-13 in KOA mice. Lipopolysaccharide (LPS) was used to induce inflammation damage in mouse chondrocytes ATDC5, and the cell viability and the expressions of NLRP3, Cleaved-Caspase-1, GSDMD-N, IL-18, and IL-1β were examined. We found that FLS-EV treatment mitigated the knee-joint damage and symptoms of KOA mice, decreased MMP-3 and MMP-13, and inhibited pyroptosis of chondrocytes in DMM mice and LPS-induced ATD5 cells. Then, Cy3-labeled miR-25-3p in mice chondrocytes was observed and the expressions and the binding relation of miR-25-3p and cytoplasmic polyadenylation element-binding protein 1 (CPEB1) were verified. It showed that FLS-EVs carried miR-25-3p into chondrocytes, and upregulated miR-25-3p expression while inhibited CPEB1 transcription, resulting in mitigation of pyroptosis of chondrocytes, and CPEB1 overexpression reversed the inhibition of FLS-EVs on pyroptosis of chondrocytes in KOA.

Ferroptosis-related genes LPCAT3 and PGD are potential diagnostic biomarkers for osteoarthritis

BackgroundOsteoarthritis (OA) is the most common chronic joint disease and how ferroptosis contributes to OA has garnered much attention recently. Bioinformatics promoted the discovery of ferroptosis-related biomarkers for OA. But since OA is a whole-joint disease, sensitive biomarkers for OA are still limited. We herein focused on subchondral bone, a joint component often-ignored by existing bioinformatic reports, to identify ferroptosis-related diagnostic biomarkers for OA.MethodMicroarray datasets GSE51588 and GSE55457 were downloaded from Gene Expression Omnibus database. Ferroptosis-related differential expression genes (Ferr-DEGs) between OA and normal samples were identified and their functional enrichment was analyzed. Common genes for OA diagnosis were selected from Ferr-DEGs using the combination of SVM-RFE, LASSO regression, and RandomForest machine learning algorithms. Common genes' diagnostic value was verified by receiver operating characteristic (ROC) curve and their association with immune infiltration was analyzed by CIBERSORT. Finally, candidate gene’s expression was verified in chondrocytes from OA patients and in an in vitro IL-1β-induced OA model, by RT-PCR.ResultsTwo ferroptosis-related genes, LPCAT3 and PGD, were identified as OA diagnostic biomarkers and confirmed by ROC diagnostic test. The association of LPCAT3 and PGD with the infiltration of several types of immune cells was identified. The decreased expression of LPCAT3 and PGD was both confirmed in OA chondrocytes and IL-1β-induced OA condition.ConclusionsWe identified ferroptosis-related genes LPCAT3 and PGD as potential diagnostic biomarkers for OA, which may offer insight into the role of ferroptosis in OA and provides useful information for the diagnosis and treatment of OA.

Effects of low-intensity exercise on spontaneously developed knee osteoarthritis in male senescence-accelerated mouse prone 8

BackgroundOsteoarthritis (OA) is a degenerative joint disease associated with aging, which often leads to joint stiffness and disability. Exercise is one of the most important non-pharmacological treatments and is prescribed as an indispensable treatment for OA. However, whether physical exercise is beneficial for preventing the progression of OA symptoms with age is poorly understood. We investigated the effects of exercise on spontaneously developed knee OA using male senescence-accelerated mouse prone 8 (SAMP8).MethodsTo examine age-related changes in the knee joints of SAMP8, knee articular cartilage changes, synovitis, knee joint flexion and extension angles, swelling, walking ability, and quadriceps muscle atrophy were analyzed at 3, 5, 7, and 9 months. SAMP8 were required to run at a speed of 10 m/min for 15 min/day from 7 to 9 months of age. The knee joint pathologies and symptoms of exercising and non-exercising mice were compared by histological, immunohistochemical, and morphometrical analyses.ResultsThe mice presented with various histological changes, including cartilage destruction, osteocyte formation, synovitis, declined joint angles, and swelling. Notably, medial and posterior cartilage destruction was more severe than that of the lateral and anterior cartilage. Knee joint angles were significantly correlated with the histological scores (modified Mankin and OARSI, osteophyte formation and synovial lining cell layer). Exercise did not attenuate cartilage degeneration in the medial and posterior tibial plateau, although the articular cartilage of the anterior and lateral tibial plateau and its histological scores was remained and significantly improved, respectively, by exercise. Exercise suppressed the age-related decline of collagen type II-positive areas in the remaining articular cartilage and improved the OA symptoms. Exercise reduced the expression of monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α positive macrophages in the synovium.ConclusionThis study revealed that SAMP8 developed spontaneous knee OA with age, which resembled the disease symptoms in humans. Low-intensity exercise temporarily alleviated degeneration of the remaining cartilage, synovitis, and age-related decreases in knee flexion angle, stride length, and muscle atrophy in SAMP8. However, exercise during OA progression with age may cause mechanical stress that could be both beneficial and detrimental to joint health.

S6-3 Barriers, facilitators and strategies to implement physical activity advice and referral to exercise therapy for people with hip and knee OA in primary care

Abstract Aim Osteoarthritis (OA) is one of the most common diseases in the Netherlands. Most people with OA are seen in primary care. Core treatment for knee and hip OA in general practice is information and advice on physical activity and referral to exercise therapy. All Dutch guidelines on osteoarthritis recommend exercise therapy before a referral to secondary care. Despite the guidelines, only around 60% of the people on the waiting list for a replacement surgery have received exercise therapy. This study aims to provide insight in barriers and facilitators of General Practitioners (GPs) and possible strategies for advice on physical activity and referral to exercise therapy for people with knee and hip OA. Method A literature searched was conducted to identify barriers and facilitators of healthcare professionals (HCPs) to give people with OA advice about being physically active and refer them to exercise therapy. In two focus groups with GPS the identified barriers and facilitators were discussed and prioritized. A third focus group was used to prioritize the barriers and facilitators. The prioritized barriers and facilitators were classified within the Consolidated Framework for Implementation Research (CFIR). In a third meeting the prioritizing was checked and the first ideas for strategies, based on the Expert Recommendations for Implementing Change (ERIC) tool, were discussed. Results Barriers and facilitators out of seven papers were discussed. Most important barriers found in two focus groups (N = 12) were: time, lack of uniform information of HCPs, and cooperation between different HCPs. In the third meeting with other GPs (N = 32) different barriers in addition to the existing barriers, were mentioned: doubts about effectivity and patients’ expectations. Ideas about strategies based on the ERIC tool were education, involvement of patients, organizing regional meetings with different HCPs. Conclusion Different barriers were mentioned as most important in the focus groups, but all GPs agreed on the importance of the barrier of cooperation with different HCPs and uniform information to people with OA. Strategies that will be further developed, tested and evaluated are education for HCPs, organizations of interprofessional regional meetings and development of uniform information for people with OA.

Downregulation of lncRNA NEAT1 interacts with miR-374b-5p/PGAP1 axis to aggravate the development of osteoarthritis

BackgroundOsteoarthritis (OA), characterized by inflammation and articular cartilage degradation, is a prevalent arthritis among geriatric population. This paper was to scrutinize the novel mechanism of long noncoding RNA (lncRNA) NEAT1 in OA etiology.MethodsA total of 10 OA patients and 10 normal individuals was included in this study. Cell model of OA was built in human normal chondrocytes induced by lipopolysaccharide (LPS). An OA Wistar rat model was established through intra-articular injection of L-cysteine and papain mixtures (proportion at 1:2) into the right knee. Quantitative reverse transcription-polymerase chain reaction was employed to ascertain the expression levels of NEAT1, microRNA (miR)-374b-5p and post-GPI attachment to protein 1 (PGAP1), while dual-luciferase reporter experiments were used for the validation of target relationship among them. Cell cycle and apoptosis were calculated by flow cytometry analysis. CCK-8 assay was done to evaluate the proliferative potentials of chondrocytes. The levels of cell cycle-related proteins (Cyclin A1, Cyclin B1 and Cyclin D2) and pro-apoptotic proteins (Caspase3 and Caspase9) were measured by western blotting. Tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and IL-6 levels were determined via ELISA. Hematoxylin & eosin (HE) Staining was used for pathological examination in OA rats.ResultsPronounced downregulation of NEAT1 and PGAP1 and high amounts of miR-374b-5p were identified in OA patients, LPS-induced chondrocytes and OA rats. NEAT1 targeted miR-374b-5p to control PGAP1 expression. Loss of NEAT1 or upregulation of miR-374b-5p dramatically accelerated apoptosis, led to the G1/S arrest and promoted the secretion of inflammatory cytokines in LPS-induced chondrocytes, while ectopic expression of PGAP1 exhibited the opposite influences on chondrocytes. Additionally, we further indicated that upregulation of miR-374b-5p attenuated the effects of PGAP1 overexpression on LPS-induced chondrocytes.ConclusionsReduced NEAT1 induces the development of OA via miR-374b-5p/PGAP1 pathway. This suggests that the regulatory axis NEAT1/miR-374b-5p/PGAP1 is a novel and prospective target for OA treatment.

Identification of basement membrane-related biomarkers associated with the diagnosis of osteoarthritis based on machine learning

BackgroundOsteoarthritis is a very common clinical disease in middle-aged and elderly individuals, and with the advent of ageing, the incidence of this disease is gradually increasing. There are few studies on the role of basement membrane (BM)-related genes in OA.MethodWe used bioinformatics and machine learning methods to identify important genes related to BMs in OA patients and performed immune infiltration analysis, lncRNA‒miRNA-mRNA network prediction, ROC analysis, and qRT‒PCR.ResultBased on the results of machine learning, we determined that LAMA2 and NID2 were the key diagnostic genes of OA, which were confirmed by ROC and qRT‒PCR analyses. Immune analysis showed that LAMA2 and NID2 were closely related to resting memory CD4 T cells, mast cells and plasma cells. Two lncRNAs, XIST and TTTY15, were simultaneously identified, and lncRNA‒miRNA‒mRNA network prediction was performed.ConclusionLAMA2 and NID2 are important potential targets for the diagnosis and treatment of OA.

Cardamonin protects against iron overload induced arthritis by attenuating ROS production and NLRP3 inflammasome activation via the SIRT1/p38MAPK signaling pathway

Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.

Some aspects of anti-inflammatory therapy of osteoarthritis

In the article, the authors discuss the therapy of OA as one of the common diseases of the musculoskeletal system, which leads to disability of people of working age. Focusing on modern concepts of pathogenesis, the article draws attention to pain and the mechanisms of its formation in OA. The recommendations of the world’s leading communities (EULAR, ARC OARSI) and the conclusions of the consensus resolution of experts of the Russian Federation on the diagnosis and treatment of osteoarthritis 2022 are also given. The article draws attention to some aspects of pain therapy. The data of studies and meta-analyses demonstrating the effectiveness of NSAIDs in pain associated with OA are presented. Among the variety of NSAIDs, the article provides data on the efficacy and safety of nimesulide, as well as its additional properties such as inhibition of cancer cell proliferation, neuroprotective and gastroprotective effects. The conclusions of the consensus meetings of 2005, the purpose of which was to provide a continuous and up-to-date assessment of the clinical profile and safety profile of nimesulide, and 2014, the purpose of which was to familiarize with the current state of pathophysiology and treatment of acute pain with a special focus on nimesulide, are presented. The article also provides data on the safety and efficacy of nimesulide in the treatment of OA in comparison with drugs such as diclofenac, naproxen and ibuprofen. One of the little-studied aspects of pain therapy is the patient’s preference. The article presents data from studies of the effectiveness of various forms of NSAIDs and patient preferences in therapy. The authors of the article conclude that the most acceptable from the point of view of efficacy, safety, the rate of onset of the effect, as well as the preferences of patients is nimesulide in the form of granules for the preparation of a solution.

POLYACRYLAMIDE HYDROGEL VERSUS HYALURONIC ACID IN KNEE OSTEOARTHRITIS: A SUBGROUP ANALYSIS OF A RANDOMIZED STUDY

AbstractIntroductionThe effectiveness of single intra-articular injections of polyacrylamide hydrogel (iPAAG) and hyaluronic acid (HA) was compared in subgroups of participants from an RCT based on baseline age, BMI or Kellgren-Lawrence (KL) grade.Methodology239 participants were randomised to 6 mL iPAAG (Arthrosamid; n=119) or 6 mL HA (Synvisc-One; n=120). Participants continued analgesics (except 48 hours prior to visits) and non-pharmacological therapy. Topical therapies and intra-articular corticosteroids were not allowed. Pre-specified subgroup analyses (age: <70 years, ≥70 years; BMI: normal, overweight, obese; KL grade: 2, 3, 4, 2–3) of change from baseline in WOMAC pain subscale at 52 weeks were based on the least squares means for the treatment-by-week interaction effect using a mixed model for repeated measurement with a restricted maximum likelihood-based approach.ResultsAcross all patients, change from baseline in WOMAC pain subscale in the iPAAG group was non-inferior to HA at 26 weeks and approached superiority (p=0.0572) at 52 weeks. Treatment differences for change from baseline in WOMAC pain subscale in favour of iPAAG over HA were statistically significant for the age <70 years (p=0.019), BMI normal (p=0.011) and KL grade 2–3 (p=0.033) subgroups. Treatment differences for all other subgroups favoured iPAAG, except for KL grade 4 which favoured HA, without reaching statistical significance.ConclusioniPAAG approached superiority to HA across all participants at 52weeks, but demonstrated statistical superiority in participants with normal BMI, participants <70 years old or participants with KL score 2–3. iPAAG represents a useful alternative to HA for the treatment of knee OA.

Study on the mechanism of puerarin against osteoarthritis from ferroptosis based on network pharmacology and bioinformatics

Network pharmacology and bioinformatics were used to study puerarin’s molecular mechanism in treating osteoarthritis from the perspective of ferroptosis, revealing a new treatment target. Ferroptosis-related targets were obtained from FerrDb. Puerarin action targets were retrieved from TCMSP, Pharmmappe, SwissTargetPrediction, and Targetnet databases, and supplemented with PubMed. The gene expression profiles of GSE12021, GSE55235, and GSE82107 were obtained using “Osteoarthritis” as the search term in the GEO database, and the differential expression gene screening analysis was performed for osteoarthritis. The intersection targets between puerarin, iron death, and osteoarthritis were obtained using Venn diagrams. GO and KEGG analyses were conducted with R software. Molecular docking and visualization of puerarin and core targets were performed using Autodock Vina and PyMol software. The effects of puerarin on the cell viability and the TNFα, IL6, and Ilβ levels of human inflammation articular chondrocytes were tested in vitro experiments. Puerarin, ferroptosis, and osteoarthritis share four targets: PLIN2, PTGS2, VEGFA, and IL6. GO enrichment analysis showed that puerarin maintained the blood-brain barrier, regulated peptide serine phosphorylation, and had anti-inflammatory effects. KEGG analysis showed that puerarin’s anti-inflammatory effects were mainly through VEGF, IL-17, C-type lectin receptor, HIF-1, TNF, and other signaling pathways. Puerarin closely bound PLIN2, PTGS2, VEGFA, and IL6 targets in molecular docking. In vitro, puerarin prevented osteoarthritis. Network pharmacology and bioinformatics explained puerarin’s multi-target and multi-pathway treatment of OA, which may be related to ferroptosis, and confirmed its anti-inflammatory effect.

An in vitro and in vivo study: Valencene protects cartilage and alleviates the progression of osteoarthritis by anti-oxidative stress and anti-inflammatory effects

BackgroundOsteoarthritis (OA) is a heterogeneous disease involving the whole joint. The pathogenesis involves oxidative stress levels and chronic inflammation, and Valencene (VA) has excellent anti-inflammatory and antioxidant stress abilities. PurposeThe objective was to study the effects of VA therapy on combating oxidative stress and to evaluate the protective effect of chondrocytes to alleviate the progression of OA. MethodsC57BL6J mouse chondrocytes were used as the primary cells in this study. Mouse chondrocytes were stimulated with IL-1β, and VA was administered in different concentrations. Reactive oxygen species (ROS) assay kits, western blotting, cellular immunofluorescence, and scanning microscopy were used to evaluate VA's antioxidant stress mechanism, anti-inflammatory effect, and cartilage protective ability. The mouse arthritis model constructed by destabilization of medial meniscus (DMM) was observed by micro-CT scan and histology after different treatments. ResultsWe found that VA can reverse the rise of ROS under IL-1β, the degeneration of the cartilage extracellular matrix, and the production of inflammatory mediators. In terms of mechanism, VA activated NRF2/HO-1/NQO1 pathway, thus enhancing ROS clearance. The phosphorylation of IκBα is inhibited, which further reduces the downstream phosphorylation of P65 in nuclear factor-κB (NF-κB) signaling. In addition, VA inhibited mitogen-activated protein kinase (MAPK) signaling molecules P-JNK, P-ERK, and P-P38, inhibiting the production of inflammatory mediators and thus inhibiting Aggrecan and Collagen Type II （COL2）degeneration. In vivo, VA reduced DMM-induced osteophytes and spurs, suppressed subchondral bone destruction, and reduced articular cartilage erosion. ConclusionOur study demonstrated that VA is an effective candidate for OA treatment.