Treatment Of OA Research Articles

Dual effects of dulaglutide on glycemic control and knee osteoarthritis pain in elderly patients with Type 2 diabetes.

Aim: This study aims to evaluate the dual benefits of dulaglutide in improving glycemic control and reducing knee OA pain.Patients & methods: Elderly T2DM patients diagnosed with bilateral knee OA on conventional OA treatment for at least 3 months were studied for their glycemic metrics, OA pain scores and NSAID consumption at baseline, 3 months and 6 months.Results: Significant improvements in glycemic control were observed, HbA1c decreased from 8.7% to 6.5% over 6 months. Pain scores, NSAID, body weight and BMI showed substantial reductions over time. Positive correlation (r=0.73, p<0.001) was found between glycemic control and pain reduction.Conclusion: Dulaglutide improves glycemic control, knee joint OA pain and weight management in elderly patients with T2DM.

Barriers, facilitators and referral patterns of general practitioners, physiotherapists, and people with osteoarthritis to exercise

BackgroundBarriers and facilitators of general practitioners (GPs), physiotherapists (PTs), and people with hip and knee osteoarthritis (PwOA) may influence uptake of and referral to guideline-based exercise treatments for OA. ObjectiveTo identify barriers and facilitators of GPs, PTs and PwOA to uptake of and referral to exercise treatments for OA. MethodsAn online survey was circulated to GPs, PTs, and PwOA in Ireland from March to September 2021. Data were collected on demographics, barriers and facilitators, and referral patterns to exercise treatments for OA. Frequency distributions were used to illustrate demographics, barriers and facilitators, and referral patterns to exercise treatments for OA. Results388 stakeholders responded (GPs = 148; PTs = 154; PwOA = 86). Barriers and facilitators were related to (1) stakeholder (e.g., patient tiredness and fatigue), (2) healthcare setting (e.g., appropriate referrals from GP or other sources), and (3) treatment (e.g., low-cost community-based exercise programmes) factors. While 91% of GPs would refer PwOA to physiotherapy if no barriers existed, only 60% would in their current practice. Only 33% of PwOA reported receiving a GP referral to physiotherapy. ConclusionStakeholder, healthcare setting and treatment barriers and facilitators of GPs, PTs, and PwOA influence uptake of and referral to exercise treatments for OA. Future strategies Future strategies addressing these factors may improve implementation of guideline-based management for OA. Contribution of the Paper•Despite an established evidence-based consensus, uptake of and referral to exercise as a first-line treatment for OA is suboptimal, partly influenced by the barriers and facilitators of stakeholders (e.g., GPs, PTs, and PwOA).•Barriers and facilitators that influence uptake of and referral to exercise treatments for OA are related to stakeholder, healthcare setting, and treatment factors.•Majority of PwOA are not receiving GP referrals to physiotherapy, and a mismatch between GPs intentions to and actual referrals to physiotherapy exists, primarily due to long waitlists to access services.•These findings may be adapted to inform strategies for the successful implementation of exercise treatments that are effective in encouraging guideline-based management of OA.

Evaluation of the effect of low-intensity pulsed ultrasound in pain and dysfunction for knee osteoarthritis: a double-blind, randomised controlled trial protocol

IntroductionOsteoarthritis (OA) is the most common joint disorder among musculoskeletal conditions. Non-surgical treatment is the standard therapy for knee OA (KOA). Ultrasound therapy is recommended for alleviating pain and dysfunction...

Identification of biomarkers related to tryptophan metabolism in osteoarthritis

BackgroundOA (osteoarthritis) is a common joint disease characterized by damage to the articular cartilage and affects the entire joint tissue, with its main manifestations being joint pain, stiffness, and limited movement.Currently,we know that OA is a complex process composed of inflammatory and metabolic factors.It is reported that the occurrence and development of OA is related to the change of tryptophan metabolism.Therefore, the study of tryptophan metabolism and OA related genes is hopeful to find a new therapeutic target for OA. MethodsDifferentially expressed genes (DEGs) in GSE55235 were gained via differential expression analysis (OA samples vs normal samples). The tryptophan metabolic related DEGs (TMR-DEGs) were obtained by overlapping tryptophan metabolism related genes (TMRGs) and DEGs. Further, biomarkers were screening via Least absolute shrinkage and selection operator (LASSO), naive bayes (NB) and supportvector machine-recursive feature elimination (SVM-RFE) algorithm to establish a diagnostic model. Afterward, Gene Set Enrichment Analysis (GSEA) and drug prediction were performed based on diagnostic biomarkers by multiple software and databases. Eventually, expression level of biomarker public databases was verified using real-time quantitative polymerase chain reaction (RT-qPCR). ResultsThree tryptophan metabolism related biomarkers (TDO2, AOX1 and SLC3A2) were identified in OA. GSEA analysis demonstrated that biomarkers were associated with the function of ‘FoxO signaling pathway’, ‘spliceosome’ and ‘ribosome’. There were seven drugs with therapeutic potential on TDO2 and AOX1. Ultimately, compared with normal group, expression of AOX1 and SLC3A2 in OA group remarkable lower. ConclusionOverall, three tryptophan metabolic related diagnostic biomarkers that associated with OA were obtained, which provided a original direction for the diagnosis and treatment of OA.

Sargassum polysaccharide attenuates osteoarthritis in rats and is associated with the up-regulation of the ITGβ1-PI3K-AKT signaling pathway

BackgroundOsteoarthritis (OA) presents a formidable challenge, characterized by as-yet-unclear mechanical intricacies within cartilage and the dysregulation of bone homeostasis. Our preliminary data revealed the encouraging potential of a Sargassum polysaccharide (SP), in promoting chondrogenesis. The aim of our study is to comprehensively assess the therapeutic effects of SP on OA models and further elucidate its potential mechanism. MethodsThe protective effects of SP were initially evaluated in an inflammation-induced human chondrocyte (C28) cell model. CCK-8 assays, Alcian blue staining, RT-qPCR and Western blotting were used to verify the chondrogenesis of SP in vitro. To assess the efficacy of SP in vivo, surgically induced medial meniscus destabilization (DMM) OA rats underwent an 8-week SP treatment. The therapeutic effects of SP in OA rats were comprehensively evaluated using X-ray imaging, micro-computed tomography (μ-CT), histopathological analysis, as well as immunohistochemical and immunofluorescent staining. Following these assessments, we delved into the potential signaling pathways of SP in inflammatory chondrocytes utilizing RNA-seq analysis. Validation of these findings was conducted through RT-qPCR and western blotting techniques. ResultsSP significantly enhance the viability of C28 chondrocytes, and increased the secretion of acidic glycoproteins. Moreover, SP stimulated the expression of chondrogenic genes (Aggrecan, Sox9, Col2a1) and facilitated the synthesis of Collagen II protein in C28 inflammatory chondrocytes. In vivo experiments revealed that SP markedly ameliorated knee joint stenosis, alleviated bone and cartilage injuries, and reduced the histopathological scores in the OA rats. μ-CT analysis confirmed that SP lessened bone impairments in the medial femoral condyle and the subchondral bone of the tibial plateau, significantly improving the microarchitectural parameters of the subchondral bone. Histopathological analyses indicated that SP notably enhanced cartilage quality on the surface of the tibial plateau, leading to increased cartilage thickness and area. Immunohistochemistry staining and immunofluorescence staining corroborated these findings by showing a significant promotion of Collagen II expression in OA joints treated with SP. RNA-seq analysis suggest that SP's effects were mediated through the regulation of the ITGβ1-PI3K-AKT signaling axis, thereby stimulating chondrogenesis. Verification through RT-qPCR and Western blot analyses confirmed that SP significantly upregulated the expression of ITGβ1, p110δ, AKT1, ACAN, and Col2a1. Notably, knock-down of ITGβ1 using siRNA in C28 chondrocytes inhibited the expression of ITGβ1, p110δ, AKT1, and ACAN. However, these inhibitory effects were not completely reversed by supplemental SP intervention. ConclusionsIn summary, our findings reveal that SP significantly enhances chondrogenesis both in vitro and in vivo, alleviating OA progression both in bone and cartilage. The observed beneficial effects are intricately linked to the activation of the ITGβ1-PI3K-AKT signaling axis. The translational potential of this articleOur research marks the first instance unveiling the advantageous effects and underlying mechanisms of SP in OA treatment. With its clinical prospects, SP presents compelling new evidence for the advancement of a next-generation polysaccharide drug for OA therapy.

Microalgae‐Based Dual Drug Delivery System with Enhanced Articular Cavity Retention for Osteoarthritis Treatment

AbstractOsteoarthritis (OA) is a prevalent degenerative joint disease globally, and the availability of effective treatments for OA remains limited. Recent research has shown that metformin offers pleiotropic advantages in the development of OA. However, the therapeutic effects of metformin are hindered by inadequate residence time within the joints, instability, and low bioavailability. In this study, the utilization of natural microalgae S. platensis (SP) is proposed as carriers for metformin, resulting in the development of a metformin delivery system (SP@Met) as a dual drug delivery system that exhibits responsive dual drug cascade release and improved retention within the articular cavity. The local administration of SP@Met has demonstrated efficacy in extending the drug retention time within the articular cavity, while also enabling cascade release of both metformin and phycocyanin. SP@Met can effectively eliminate reactive oxygen species, reduce the expression of pro‐inflammatory cytokines, and restore the balance of cartilage anabolism and catabolism, thereby impeding the progression of OA. This therapeutic approach utilizes a natural microalgae carrier to facilitate efficient delivery of metformin to the articular cavity, resulting in synergistic therapeutic efficacy and offering a promising avenue for the management of OA for potential clinical application.

Attenuation of osteoarthritis progression via locoregional delivery of Klotho-expressing plasmid DNA and Tanshinon IIA through a stem cell-homing hydrogel

BackgroundOsteoarthritis (OA) is an aging-related degenerative joint disorder marked by joint discomfort and rigidity. Senescent chondrocytes release pro-inflammatory cytokines and extracellular matrix-degrading proteins, creating an inflammatory microenvironment that hinders chondrogenesis and accelerates matrix degradation. Targeting of senescent chondrocytes may be a promising approach for the treatment of OA. Herein, we describe the engineering of an injectable peptide-hydrogel conjugating a stem cell–homing peptide PFSSTKT for carrying plasmid DNA-laden nanoparticles and Tanshinon IIA (pPNP + TIIA@PFS) that was designed to attenuate OA progression by improving the senescent microenvironment and fostering cartilage regeneration.ResultsSpecifically, pPNP + TIIA@PFS elevates the concentration of the anti-aging protein Klotho and blocks the transmission of senescence signals to adjacent healthy chondrocytes, significantly mitigating chondrocyte senescence and enhancing cartilage integrity. Additionally, pPNP + TIIA@PFS recruit bone mesenchymal stem cells and directs their subsequent differentiation into chondrocytes, achieving satisfactory chondrogenesis. In surgically induced OA model rats, the application of pPNP + TIIA@PFS results in reduced osteophyte formation and attenuation of articular cartilage degeneration.ConclusionsOverall, this study introduces a novel approach for the alleviation of OA progression, offering a foundation for potential clinical translation in OA therapy.

Increased Cellular Dosage of Bone Marrow Aspiration Concentrate Does Not Translate to Increased Clinical Effectiveness in Knee Osteoarthritis: A Phase I Dose Escalation Study.

Knee osteoarthritis (KOA), a chronic degenerative disease, significantly impairs quality of life due to pain and mobility limitations. Traditional treatments focus on symptom management without addressing the underlying disease progression, leading to a growing interest in regenerative medicine approaches. Bone marrow aspirate concentrate (BMAC), rich in mesenchymal stem cells and growth factors, has shown potential for cartilage repair and symptom relief in KOA. Despite promising outcomes, the optimal BMAC dosage for knee OA treatment remains undetermined. This study aims to evaluate the clinical efficacy and safety of varying BMAC dosages in knee OA treatment. This prospective controlled dose-escalation study involved 75 patients with early-stage knee OA, categorized into three groups based on BMAC dosage administered 10 × 106 cells (low-dose group), 50 × 106 cells (medium-dose group), or 100 × 106 cells (high-dose group). All the patients underwent a single intra-articular injection of BMAC and were monitored over a year. The primary outcomes include Visual Analog Scale (VAS) for pain and the Knee Injury and Osteoarthritis Outcome Score (KOOS) for joint function recorded at baseline, 1, 3, 6, and 12months post-intervention. Adverse events were also documented. Significant clinical improvements in VAS and KOOS scores were noted across all groups at all time points compared to the baseline. However, these improvements did not significantly differ between dosage groups throughout the follow-up period. Adverse effects were minimal and primarily consisted of transient post-injection pain and effusion, with no dose-dependent increase in complications. BMAC treatment for knee OA is safe and demonstrates potential for significant pain relief and functional improvement, irrespective of the dosage administered within the tested range. The lack of significant differences among varying dosages suggests a plateau in therapeutic efficacy beyond a certain threshold. Further research is necessary on the long-term outcomes to optimize the dosing strategy.

ROS-induced imbalance of the miR-34a-5p/SIRT1/p53 axis triggers chronic chondrocyte injury and inflammation

Osteoarthritis is a chronic degenerative disease based on the degeneration and loss of articular cartilage. Inflammation and aging play an important role in the destruction of the extracellular matrix, in which microRNA (miRNA) is a key point, such as miRNA-34a-5p. Upregulation of miRNA-34a-5p was previously reported in a rat OA model, and its inhibition significantly suppressed interleukin (IL)-1β-induced apoptosis in rat chondrocytes. However, Oxidative stress caused by reactive oxygen species (ROS) can exacerbate the progression of miRNA regulated OA by mediating inflammatory processes. Thus, oxidative stress effects induced via tert-butyl hydroperoxide (tBHP) in human chondrocytes were assessed in the current research by evaluating mitochondrial ROS production, mitochondrial cyclooxygenase (COX) activity, and cell apoptosis. We also analyzed the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD). Additionally, inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and IL-24, which contribute to OA development, were detected by enzyme-linked immunosorbent assay (ELISA). The results of this study indicated that miR-34a-5p/silent information regulator 1 (SIRT1)/p53 axis was involved in the ROS-induced injury of human chondrocytes. Moreover, dual-luciferase assay revealed that SIRT1 expression was directly regulated by miR-34a-5p, indicating the presence of a positive feedback loop in the miR-34a-5p/SIRT1/p53 axis that plays an important role in cell survival. However, ROS disrupted the miR-34a-5p/SIRT1/p53 axis, leading to the development of OA, and articular injection of SIRT1 agonist, SRT1720, in a rat model of OA effectively ameliorated OA progression in a dose-dependent manner. Our study confirms that miRNA-34a-5p could participate in oxidative stress responses caused by ROS and further regulate the inflammatory process via the SIRT1/p53 signaling axis, ultimately affecting the onset of OA, thus providing a new treatment strategy for clinical treatment of OA.

Vertical Mesh-Mediated Fascial Traction and Negative Pressure Wound Therapy: A Case Series of Nine Patients in General and Vascular Surgery.

Two patients in a vascular surgery unit and seven patients in an abdominal surgery unit with an OA were treated with VMMFT in combination with NPWT between September 2019 and June 2023. A DFC was achieved in seven of nine cases. The mean duration of OA was 9.6 ± 3.8 days, and fascial dehiscence at the beginning of OA was 14.2 ± 4.0 cm on average. Time to DFC after VMMFT was established was 6.2 ± 3.5 days (mean). No method-related complications occurred. The standardized combination of VMMFT and NPWT gave positive results in achieving DFC in our heterogenic patient group. Following a strict treatment pathway as shown here seems to improve OA outcome. It represents a promising further development of mesh-mediated fascial traction for OA treatment.

Bio-nanoparticles loaded with synovial-derived exosomes ameliorate osteoarthritis progression by modifying the oxidative microenvironment

Background and aimsOsteoarthritis (OA) is a prevalent degenerative joint disorder, marked by the progressive degeneration of joint cartilage, synovial inflammation, and subchondral bone hyperplasia. The synovial tissue plays a pivotal role in cartilage regulation. Exosomes (EXOs), small membrane-bound vesicles released by cells into the extracellular space, are crucial in mediating intercellular communication and facilitating the exchange of information between tissues. Our study aimed to devise a hydrogel microsphere infused with SOD3-enriched exosomes (S-EXOs) to protect cartilage and introduce a novel, effective approach for OA treatment.Materials and methodsWe analyzed single-cell sequencing data from 4247 cells obtained from the GEO database. Techniques such as PCR, Western Blot, immunofluorescence (IF), and assays to measure oxidative stress levels were employed to validate the cartilage-protective properties of the identified key protein, SOD3. In vivo, OA mice received intra-articular injections of S-EXOs bearing hydrogel microspheres, and the effectiveness was assessed using safranine O (S.O) staining and IF.ResultsSingle-cell sequencing data analysis suggested that the synovium influences cartilage via the exocrine release of SOD3. Our findings revealed that purified S-EXOs enhanced antioxidant capacity of chondrocytes, and maintained extracellular matrix metabolism stability. The S-EXO group showed a significant reduction in mitoROS and ROS levels by 164.2% (P < 0.0001) and 142.7% (P < 0.0001), respectively, compared to the IL-1β group. Furthermore, the S-EXO group exhibited increased COL II and ACAN levels, with increments of 2.1-fold (P < 0.0001) and 3.1-fold (P < 0.0001), respectively, over the IL-1β group. Additionally, the S-EXO group showed a decrease in MMP13 and ADAMTS5 protein expression by 42.3% (P < 0.0001) and 44.4% (P < 0.0001), respectively. It was found that S-EXO-containing hydrogel microspheres could effectively deliver SOD3 to cartilage and significantly mitigate OA progression. The OARSI score in the S-EXO microsphere group markedly decreased (P < 0.0001) compared to the OA group.ConclusionThe study demonstrated that the S-EXOs secreted by synovial fibroblasts exert a protective effect on chondrocytes, and microspheres laden with S-EXOs offer a promising therapeutic alternative for OA treatment.

Combinatory Nanovesicle with siRNA-Loaded Extracellular Vesicle and IGF-1 for Osteoarthritis Treatments.

Extracellular vesicles (EVs) have been found to have the characteristics of their parent cells. Based on the characteristics of these EVs, various studies on disease treatment using mesenchymal stem cell (MSC)-derived EVs with regenerative activity have been actively conducted. The therapeutic nature of MSC-derived EVs has been shown in several studies, but in recent years, there have been many efforts to functionalize EVs to give them more potent therapeutic effects. Strategies for functionalizing EVs include endogenous and exogenous methods. In this study, human umbilical cord MSC (UCMSC)-derived EVs were selected for optimum OA treatments with expectation via bioinformatics analysis based on antibody array. And we created a novel nanovesicle system called the IGF-si-EV, which has the properties of both cartilage regeneration and long-term retention in the lesion site, attaching positively charged insulin-like growth factor-1 (IGF-1) to the surface of the UCMSC-derived Evs carrying siRNA, which inhibits MMP13. The downregulation of inflammation-related cytokine (MMP13, NF-kB, and IL-6) and the upregulation of cartilage-regeneration-related factors (Col2, Acan) were achieved with IGF-si-EV. Moreover, the ability of IGF-si-EV to remain in the lesion site for a long time has been proven through an ex vivo system. Collectively, the final constructed IGF-si-EV can be proposed as an effective OA treatment through its successful MMP13 inhibition, chondroprotective effect, and cartilage adhesion ability. We also believe that this EV-based nanoparticle-manufacturing technology can be applied as a platform technology for various diseases.

3D-bioprinted anti-senescence organoid scaffolds repair cartilage defect and prevent joint degeneration via miR-23b/ELOVL5-mediated metabolic rewiring

IntroductionOsteoarthritis (OA) is the most prevalent degenerative disease worldwide and commonly occurs among the elderly. At present, there is no effective treatment for OA. When OA develops to the end stage, arthroplasty is generally operated to improve the life quality of patients. Targeting senescence has been considered as a therapeutic approach for OA in recent years. Methods & resultsIn this study, we have identified P16 gene as a novel target for anti-senescence strategy and harnessed small interfering RNA (siRNA) technology to fabricate P16-siRNA encapsulated PLGA microspheres. We combined this with our previously successful three-dimensional (3D) culture of functionally bioengineered chondrogenic synovial mesenchymal stromal cell (SMSC) organoids. This served as the primary component of the bio-ink for 3D bioprinting, culminating in the creation of P16-siRNA PLGA µS and SMSC organoid hydrogel-polymer composite scaffold (PPSOH). Its superior capabilities of cartilage repair were confirmed through in vivo and in vitro experimentations. In the rabbit model of knee cartilage defects, PPSOH not only restored the superior characteristics of native healthy hyaline cartilage but also maintained post-implanted joint function. It prevented development of joint degeneration resulting from cartilage defects by mitigating intra-articular inflammatory responses and cellular senescence. Our usage of miRNA and RNA sequencing reveals that PPSOH targets the miR-23b/ELOVL5 axis and rewired cellular metabolism, therefore regulating glycolysis and fatty acid oxidation. This effectively alleviates cellular senescence, promotes relief from OA, and facilitates cartilage regeneration. ConclusionPPSOH scaffold could effectively alleviate cellular senescence, foster relief from OA, and facilitate cartilage regeneration. Further experiments disclosed that PPSOH targets the miR-23b/ELOVL5 axis and rewired cellular metabolism by regulating glycolysis and fatty acid oxidation. Therefore, PPSOH could be used as potential therapy for cartilage repair in osteoarthritic patients.

Evidence of the clinical effect of commonly used intra‐articular treatments of equine osteoarthritis

SummaryBackgroundOsteoarthritis (OA) is a common disease in equine patients that causes joint pain and loss of function. The aetiology of OA is assumed to be multifactorial. A range of medical treatments are on the market for symptomatic treatment of OA in equine patients, both biological and conventional options. Today, no true disease‐modifying osteoarthritis drug (DMOAD) is available.ObjectiveTo summarise the current evidence of the clinical effect of commonly used intra‐articular treatments of equine OA, specifically the use of intra‐articular glucocorticosteroids (IA‐GCs), intra‐articular hyaluronic acid (IA‐HA), intra‐articular platelet‐rich plasma/autologous‐conditioned plasma (IA‐PRP), intra‐articular interleukin‐1 receptor antagonist protein/autologous‐conditioned serum (IA‐IRAP) and intra‐articular mesenchymal stem cells (IA‐MSCs).Study designSystematic review.MethodsUsing the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis (PRISMA) guidelines, a comprehensive search identified 22 clinical studies where horses with OA, naturally occurring or induced, were treated with one of the mentioned intra‐articular treatments. The studies were reviewed to collect all in vivo studies with clinical follow‐up on horses with OA.ResultsIA‐GCs seem to have a beneficial short‐term clinical outcome. Treatment with IA‐HA shows varying clinical results and provides uncertain evidence for a beneficial clinical effect. IA‐PRP shows overall promising clinical results for a significant improvement. IA‐IRAP shows promising significant clinical effect, but most of the studies lack a control group for comparison. IA‐MSCs show varying clinical results, but a majority of the included studies show evidence for a significant improvement in clinical effect.ConclusionTo provide stronger evidence of the clinical effect of the five chosen treatments, further blinded, randomised and placebo‐controlled studies are needed.

Intra‐Articular Injection of Nanomaterials for the Treatment of Osteoarthritis: From Lubrication Function Restoration to Cell and Gene Therapy

AbstractOsteoarthritis (OA), a prevalent joint disease affecting many people globally, presents significant challenge in current treatments, which often only manage symptoms without halting disease progression. This review illuminates novel approaches in OA therapy, focusing mainly on intra‐articular injection of nanomaterials. The innovative materials, designed to either mimic or augment natural joint lubrication, show promise in restoring joint biomechanics and alleviating pain. The review delves into an array of biomimetic lubricants, including polymer brush, nanocomposite hydrogel, and nanoparticles, underscoring their roles in anti‐inflammation, targeting, cartilage repair, and drug delivery. Furthermore, the potential of mesenchymal stem cells to differentiate into chondrocytes, coupled with the delivery of these cells and their exosomes via nanomaterials, has promoted cell therapy avenues for OA. The review also highlights the function of non‐coding RNAs such as miRNA, siRNA, circRNA, lncRNA, and antisense oligonucleotides in impeding OA progression, with nanomaterials facilitating their delivery, thus facilitating advanced therapeutic possibilities including immune evasion and bone cell proliferation. Overall, this review encapsulates the evolution of nanomaterials in OA treatment from material to cell, and ultimately to gene therapy, forecasting a future where nanomaterials evolve toward integrated, personalized diagnostics and therapeutics for OA.

Interplay between lipid dysregulation and ferroptosis in chondrocytes and the targeted therapy effect of metformin on osteoarthritis

IntroductionOsteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide; the role of lipid dysregulation in OA and mechanisms underlying targeted therapy effect of lipid-lowering metformin on OA remains poorly defined. ObjectivesTo investigate the effects of lipid dysregulation on OA progression and to explore lipid dysregulation-targeting OA treatment of metformin. MethodsRNA-Seq data, biochemical, and histochemical assays in human and murine OA cartilage as well as primary chondrocytes were utilized to determine lipid dysregulation. Effects of metformin, a potent lipid-lowering medication, on ACSL4 expression and chondrocyte metabolism were determined. Further molecular experiments, including RT-qPCR, western blotting, flow cytometry, and immunofluorescence staining, were performed to investigate underlying mechanisms. Mice with intra-articular injection of metformin were utilized to determine the effects on ACLT-induced OA progression. ResultsACSL4 and 4-HNE expressions were elevated in human and ACLT-induced mouse OA cartilage and IL-1β-treated chondrocytes (P < 0.05). Ferrostatin-1 largely rescued IL-1β-induced MDA, lipid peroxidation, and ferroptotic mitochondrial morphology (P < 0.05). Metformin decreased the levels of OA-related genes (P < 0.05) and increased the levels of p-AMPK and p-ACC in IL-1β-treated chondrocytes. Intra-articular injection of metformin alleviated ACLT-induced OA lesions in mice, and reverted the percentage of chondrocytes positive for MMP13, Col2a1, ACSL4 and 4-HNE in ACLT mice (P < 0.05). Ferroptotic chondrocytes promoted the recruitment and chemotaxis of RAW264.7 cells via CCL2, which was blocked by metformin in vitro (P < 0.05). ConclusionWe establish a critical role of polyunsaturated fatty acids metabolic process in OA cartilage degradation and define metformin as a potential OA treatment. Metformin reshapes lipid availability and ameliorates chondrocyte ferroptosis sensitivity via the AMPK/ACC pathway. In the future, gene-edited animals and extensive omics technologies will be utilized to reveal detailed lipids’ involvement in cartilage lesions.

404 Mechanisms of a Dynamic Stability Protocol for Persons with Thumb Osteoarthritis

OBJECTIVES/GOALS: Our aims are to 1) describe changes in thumb Carpometacarpal (CMC1) joint stability following an 8-week clinic-based dynamic stability exercise program using computerized tomography (CAT) and 2) to evaluate the agreement between ultrasound and CAT (reference standard) when quantifying thumb CMC stability. METHODS/STUDY POPULATION: Aim 1: We have enrolled 13/49 participants in a prospective pre-post interventional study of an 8-week clinic-based occupational therapy dynamic stability program. The primary outcome will be change in stability (thumb metacarpal subluxation in mm) when forcefully loading the thumb as per CAT from pre-treatment to post-treatment at 9 weeks. Aim 2: Same 49 participants are undergoing a one-time ultrasound during baseline assessment. Agreement of ultrasound and CAT measurements (thumb metacarpal subluxation in mm) will be assessed by the Bland-Altman method. RESULTS/ANTICIPATED RESULTS: Exercise is a first-line treatment of CMC1 OA yet there is insufficient evidence to support this. Progression of CMC1 OA is characterized by altered joint mechanics. Joint replacement surgery may reduce pain but often worsens thumb mechanics and overall hand function. This study is the first to test the sustained biomechanical effects of non-invasive thumb exercises. Should these benefits exist, this will further support exercise as a first-tier intervention. Should ultrasound be a suitable proxy for CAT, therapists/physicians could monitor thumb CMC mechanics in response to treatment without risk of radiation exposure. We anticipate 1) a statistically significant reduction in thumb CMC subluxation at 9 weeks follow up and 2) high agreement between sonographic and CAT measures of thumb stability. DISCUSSION/SIGNIFICANCE: This study will lay the foundation for future work and may offer critical support for the use of a non-pharmacological and non-surgical approach as first-line treatment of a highly disabling disease. Future study should include controlled trials where hand function, activity limitation, disease progression, and costs are the outcomes in interest.

Oxalic acid alleviates chilling injury and positively influences post-harvest parameters of sweet bell pepper by affecting glycine betaine accumulation, cells respiration rate and NADPH oxidase enzyme activity during cold storage

Bell pepper as tropical crop and warm-season vegetable is sensitive to cold storage under temperatures below 7.5 °C. The purposes of the current study were to investigate the influence of pre-harvest treatment of oxalic acid (OA 0, 1, 5, 10, and 15 mM) on some of most important morphological, physiological and bio-chemical characteristics of red bell pepper cv. "2090 Westland" at post-harvest stage, and assessment of mechanisms and enzymatic pathways of crop response to OA treatments. OA treatments greatly reduced the chilling index, and the positive effects of treatments enhanced by increasing the concentration of OA. The energy level (ATP content) of pepper fruits decreased with extending storage duration, but OA treatment maintained the ATP content of fruits. On 24 d of storage, the highest and lowest activity rate of NADPH oxidase enzyme was recorded in control and 10 mM-treated fruits. Extending storage duration led to a significant increase in cells respiration rate, but this increase was more pronounced in control. Oxalic acid as low-risk and environmentally friendly compound could be an appropriate choice to apply as pre-harvest treatment in order to extend shelf-life of bell pepper fruits during cold storage under 4 ºC. The most important mechanisms reaction of OA are enhancing of enzymatic and non-enzymatic antioxidant activities, increasing the accumulation rate of osmoprotectants and regulation of energy metabolism of cells. Pre-harvest treatment of OA 10 mM could be introduced as efficient technique to overcome adverse effects of chilling stress on post-harvest characteristics of bell pepper.

Effects of intra-articular injection of platelet-rich plasma on the inflammatory process and histopathological characteristics of cartilage and synovium in animals with osteoarthritis: a systematic review with meta-analysis

BackgroundOsteoarthritis (OA) affects the entire joint, causing structural changes in articular cartilage, subchondral bone, ligaments, capsule, synovial membrane, and periarticular muscles that afflicts millions of people globally, leading to persistent pain and diminished quality of life. The intra-articular use of platelet-rich plasma (PRP) is gaining recognition as a secure therapeutic approach due to its potential regenerative capabilities. However, there is controversial clinical data regarding efficacy of PRP for OA treatment. In this context, gathering scientific evidence on the effects of PRP in treating OA in animal models could provide valuable insights into understanding its impact on aspects like cartilage health, synovial tissue integrity, and the inflammatory process in affected joints. Thus, the objective of this study was to assess the effects of PRP injections on inflammation and histopathological aspects of cartilage and synovium in animal models of OA through a comprehensive systematic review with meta-analysis.MethodsA electronic search was conducted on Medline, Embase, Web of Science, The Cochrane Library, LILACS, and SciELO databases for relevant articles published until June 2022. A random-effects meta-analysis was employed to synthesize evidence on the histological characteristics of cartilage and synovium, as well as the inflammatory process. The GRADE approach was utilized to categorize the quality of evidence, and methodological quality was assessed using SYRCLE’s RoB tool.ResultsTwenty-one studies were included in the review, with twelve of them incorporated into the meta-analysis. PRP treatment demonstrated superior outcomes compared to the control group in terms of cartilage histology (very low quality; p = 0.0002), synovium histology (very low quality; p < 0.0001), and reductions in proinflammatory markers, including IL-1 (low quality; p = 0.002), IL-6 (very low quality; p < 0.00001), and TNF-α (very low; p < 0.00001). However, PRP treatment did not yield a significant impact on PDGF-A levels (very low quality; p = 0.81).ConclusionPRP appears capable of reducing proinflammatory markers (IL-1, IL-6, TNF-α) and mitigating cartilage and synovium damage in animals with OA. However, the levels of evidence of these findings are low to very low. Therefore, more rigorous studies with larger samples are needed to improve the quality of evidence.PROSPERO registrationCRD42022250314

Effects of alendronate on cartilage lesions and micro-architecture deterioration of subchondral bone in patellofemoral osteoarthritic ovariectomized rats with patella-baja

BackgroundPatellofemoral osteoarthritis (PFJOA) is a subtype of knee OA, which is one of the main causes of anterior knee pain. The current study found an increased prevalence of OA in postmenopausal women, called postmenopausal OA. Therefore, we designed the ovariectomized rat model of patella baja-induced PFJOA. Alendronate (ALN) inhibits osteoclast-mediated bone loss, and has been reported the favorable result of a potential intervention option of OA treatment. However, the potential effects of ALN treatment on PFJOA in the ovariectomized rat model are unknown and need further investigation prior to exploration in the clinical research setting. In this study, the effects of ALN on articular cartilage degradation and subchondral bone microstructure were assessed in the ovariectomized PFJOA rat model for 10 weeks.MethodsPatella baja and estrogen withdrawal were induced by patellar ligament shortening (PLS) and bilateral ovariectmomy surgeries in 3-month-old female Sprague–Dawley rats, respectively. Rats were randomly divided into five groups (n = 8): Sham + V; OVX + V, Sham + PLS + V, OVX + PLS + V, OVX + PLS + ALN (ALN: 70 μg/kg/week). Radiography was performed to evaluate patellar height ratios, and the progression of PFJOA was assessed by macroscopic and microscopic analyses, immunohistochemistry and micro-computed tomography (micro-CT).ResultsOur results found that the patella baja model prepared by PLS can successfully cause degeneration of articular cartilage and subchondral bone, resulting in changes of PFJOA. OVX caused a decrease in estrogen levels in rats, which aggravated the joint degeneration caused by PFJOA. Early application of ALN can delay the degenerative changes of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent, improve and maintain the micrometabolism and structural changes of cartilage and subchondral bone.ConclusionThe early application of ALN can delay the destruction of articular cartilage and subchondral bone microstructure in castrated PFJOA rat to a certain extent.