Osteoarthritis Model Research Articles

Nanozyme-enhanced injectable hyaluronic acid-based hydrogel for the treatment of osteoarthritis

The progression of osteoarthritis (OA) is dramatically accelerated by excessive reactive oxygen species (ROS)-induced apoptosis of chondrocytes and the inflammatory response of synovial macrophages. In this study, we developed an injectable hydrogel with a catalase-mimicking nanozyme activity as a therapeutic agent for OA. In vitro experiments confirmed that the HA and peroxide-mimetic nanoenzyme-enhanced hydrogel, containing ε-polylysine/Mn1.8Co1.2O4 (ε-PLE/MnCoO) nanoparticles, continuously eliminated ROS and inflammatory cytokines while promoting the polarization of inflammatory macrophages (M1 phenotype) towards anti-inflammatory macrophages (M2 phenotype) in dysfunctional microenvironments. When used for intraarticular injections in OA models, the nanoenzyme-enhanced hydrogel effectively reduced oxidative stress by scavenging ROS and regulating the immune microenvironment. It resulted in a subsequent reduction in the expression of inflammatory factors, including MMP-13, TNF-α, IL-1β, and iNOS in both the synovium and joint fluid. Moreover, cartilage repair was enhanced by the promotion of COL-2 and SOX-9 expression in the cartilage tissue, whereas osteophyte formation in OA was reduced. This study introduced an innovative treatment strategy for the clinical management of OA, demonstrating its significant potential for application in treating OA.

Preclinical approaches to evaluate Uncaria tomentosa bark extract loaded FDOFs using osteoarthritis models

Osteoarthritis (OA) is one of the biggest global health issues, affecting two thirds of the population and cannot be fully treated to return normal function or relieve joint discomfort. Oral fast-dissolving films offer a high medication loading capacity, targeted distribution, and increasing bioavailability. The current research explores the in vitro and in vivo efficacy of oral fast-dissolving film formulations containing Uncaria tomentosa bark extract. A three-dimensional osteoarthritis (OA) model was created for in vitro assessment using first passage chrondrocytes cultured in a 1:1:3 ratio on trypsin-EDTA medium. C20A4 chondrocytes were cultured on agarose gel at 25± 5 °C in a phosphate buffer solution to create the OA agarose model. One milliliter of RPMI-1640 (10 % FBS) was used for chrondrocyte cultivation. On the third day of incubation, a 20 % (IL-1β) solution was applied, and the media was periodically changed. On the fifth day of incubation, the treated cell line received 5 μL of 0.5 % MTT reagent, and absorbance was examined at 570 nm. The effects of FDOFs on the cell lines were examined for 7, 13, 27, and 35 days (IL-1β, F5, F13 treated IL-1β injected types and Control). As a control, chondrocytes in agarose constructs were solely grown in RPMI-FBS medium without IL-1β. The arthritic effect of improved FDOFs, i.e., F5, was investigated using the GAG, HYP, and DNA quantitation assays in conjunction with a DNA content assay. Monoiodoacetate (MIA) produced arthritis models are well-established for understanding weight bearing and reaction to tactile stimuli in invivo research. Seven-week-old male wistar rats were used in the invivo technique, with celecoxib serving as the positive control and MIA as the negative control. Estimates of osteoarthritic potential were made based on the evaluation of knee thickness and discomfort. The study's findings demonstrated the effectiveness of the F5 formulation on OA models, which need for a clinical evaluation in human beings.

Knockdown of nuclear protein 1 delays pathological pro-gression of osteoarthritis through inhibiting chondrocyte ferroptosis.

To investigate the effect of nuclear protein 1 (Nupr1) on the pathological progression of osteoarthritis and its relationship with ferroptosis of chondrocytes. Chondrocytes of mouse knee were divided into small interfering RNA (siRNA) control group, small interfering RNA targeting Nupr1 (siNupr1) group, siRNA control+IL-1β group (siRNA control interference for 24 h followed by 10 ng/mL IL-1β) and siNupr1+IL-1β group (siNupr1 interference for 24 h followed by 10 ng/mL IL-1β). The protein and mRNA expressions of Nupr1 were detected by Western blotting and real-time RT-PCR. Cell proliferation viabilities were measured using the cell counting kit-8 method. The levels of ferrous ions were detected by FerroOrange staining. Lipid peroxidation levels were detected by C11-BODIPY-591 fluorescence imaging. The contents of malondialdehyde (MDA) and glutathione (GSH) were detected by enzyme-linked immunosorbent assay. The protein expressions of long-chain acyl-coenzyme A synthetase 4 (ACSL4), tumor protein 53 (P53), glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 gene (SLC7A11) were detected by Western blotting. The osteoarthritis model was constructed by destabilization of the medial meniscus (DMM) surgery in 7-week-old male C57BL/6J mice. The mice were randomly divided into 4 groups with 10 animals in each group: sham surgery (Sham)+adeno-associated virus serotype 5 (AAV5)-Short hairpin RNA (shRNA) control group, Sham+AAV5-shRNA targeting Nupr1 (shNupr1) group, DMM+AAV5-shRNA group, and DMM+AAV5-shNupr1 group. Hematoxylin and eosin staining and Safranin O-Fast Green staining were used to observe the morphological changes in cartilage tissue. The Osteoarthritis Research Society International (OARSI) osteoarthritis cartilage histopathology assessment system was used to evaluate the degree of cartilage degeneration in mice. The mRNA expressions of Nupr1, matrix metallopeptidase 13 (MMP13), a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), cyclooxygenase 2 (COX2), and glutathione peroxidase 4 (GPX4) were detected by real-time RT-PCR. In vitro experiments showed that knocking down Nupr1 alleviated the decrease of chondrocyte proliferation activity induced by IL-1β, reduced iron accumulation in mouse chondrocytes, lowered the lipid peroxidation, downregulated ACLS4 and P53 protein expression and upregulated GPX4 and SLC7A11 protein expression (all P<0.01), thereby inhibiting ferroptosis in mouse chondrocytes. Meanwhile, in vivo animal experiments demonstrated that knocking down Nupr1 delayed the degeneration of articular cartilage in osteoarthritis mice, improved the OARSI score, slowed down the degradation of the extracellular matrix in osteoarthritis cartilage, and reduced the expression of the key ferroptosis regulator GPX4 (all P<0.01). Knockdown of Nupr1 can delay the pathological progression of osteoarthritis through inhibiting ferroptosis in mouse chondrocytes.

Evaluation of serum biomarkers after intra-articular injection of rat bone marrow-derived mesenchymal stem cells in a rat model of knee osteoarthritis

Evaluation of serum biomarkers after intra-articular injection of rat bone marrow-derived mesenchymal stem cells in a rat model of knee osteoarthritis

SIRT2 Alleviates Inflammatory Response, Apoptosis, and ECM Degradation in Osteoarthritic Chondrocytes by Stabilizing PCK1.

It has been reported that Sirtuin 2 (SIRT2) prevents phosphoenolpyruvate carboxykinase 1 (PCK1) degradation, which can be involved in aging-induced osteoarthritis (OA), but the molecular mechanism of SIRT2/PCK1 in chondrocytes has not been clarified. Therefore, this study aims to explore the mechanism of SIRT2/PCK1 in chondrocyte inflammation. To establish the OA model in vitro, chondrocytes cultured with interleukin-1β (IL-1β, 10 ng/mL) and manipulation of SIRT2 and PCK1 expression in the constructed cells to elucidate the interaction between the two genes. 1,9-Dimethyl-Methylene Blue (DMMB) was used to detect cellular glycosaminoglycan (GAG) content. Inflammatory factor levels were assessed using Enzyme-linked Immunosorbent Assay (ELISA). Apoptosis was detected by osmotic dye. The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2 Associated X (Bax), Wnt Family Member 1 (Wnt1), catenin Beta 1 (β-catenin), Aggrecan, Collagen II, matrix metallopeptidase 13 (MMP-13) proteins in cells were analyzed using Western blot. PCK1 gained lower expressions in OA cell models. Overexpression of PCK1 or SIRT2 in the IL-1β chondrocyte model of inflammation promoted GAG content, inhibited apoptosis and Wnt/β-catenin protein expression, and lowered the levels of inflammatory factors. PCK1 silencing was proved to have the opposite effect. SIRT2 overexpression rescued the increased inflammation, MMP-13 expression, and apoptosis and the decreased Aggrecan and Collagen II expression caused by PCK1 silencing. PCK1 silencing also reversed the positive effects of SIRT2 overexpression on chondrocytes. SIRT2 inhibits articular chondrocyte extracellular matrix (ECM) degradation, inflammatory factor expression, and apoptosis via PCK1.

Natural synergy: Oleanolic acid-curcumin co-assembled nanoparticles combat osteoarthritis

Curcumin (Cur) is a natural polyphenol that is one of the most valuable natural products. However, its use as a functional food is limited by low water solubility, chemical instability and poor bioavailability. In this study, a supramolecular co-assembly strategy was used to construct an oleanolic acid-curcumin (OLA-Cur) co-assembly composite nano-slow-release treatment system. As a co-assembled compound, OLA is a widely present pentacyclic triterpenoid compound with multiple biological activities in the plant kingdom, which is expected to jointly alleviate the damaging effects of papain-induced mouse osteoarthritis model. The OLA-Cur NPs shows the solid core-shell structure, which can effectively improve the water solubility of Cur and OLA, and has good stability and sustained release characteristics. The analysis results show that the two compounds are mainly assembled through hydrogen bonding interactions, hydrophobic interactions, and π - π stacking interactions. The OLA-Cur NPs can inhibit the release of pro-inflammatory cytokines TNF-α, IL-6, and IL-1β induced by LPS in RAW264.7 mouse macrophages, promote the secretion of anti-inflammatory cytokine IL-10, and improve the oxidative stress index of hydrogen peroxide induced human rheumatoid arthritis synovial fibroblasts. In addition, it has a certain improvement effect on cartilage and subchondral bone damage in mouse osteoarthritis models. These findings suggest that constructing co-assembled composite nanoparticles based on pure natural compounds may break through the limitations of a variety of important nutritional ingredients in functional foods.

A Histo-Physiological Study of The Effect of Resveratrol on Osteoporosis-Induced in Rats

Using an animal model of D-galactose-induced osteoporosis (OP), the researchers examined the effects of resveratrol supplementation on body weight, alkaline phosphatase (ALP) levels and bone calcin (OC) levels and classified mice randomized into the following groups: Subgroup C (n=10): within 60 days participants will receive 1 ml of distilled water. In the D-galactose group (n=10), osteoporosis will be induced by intraperitoneal administration of 200 mg/kg/day of D-galactose for 60 consecutive days. Group R of 10 subjects will receive a dose of 25 mg/kg of oral resveratrol for 60 days.The DR group of the group of 10 subjects will receive D-galactose 200 mg/kg/day intraperitoneally in for osteoporosis and oral resveratrol at 25 mg/kg/day for 60 days. There was a distinct difference in body weight before and after OP infusion in each group in the study. The D-galactose group (D) showed significantly higher levels of ALP and OC compared with the control group. In contrast, the resveratrol group (R) showed significantly lower levels compared with the control group and the D group. Finally, the group treated with the combination of D-galactose and resveratrol (DR) showed significantly higher levels compared to the control group and the group treated with resveratrol alone (R). the. and more microfractures On the other hand, the resveratrol group (R) had thicker bone trabeculae, reduced intertrabecular space, and fewer microfractures. In addition, a protective effect against D-galactose-induced changes was observed in the resveratrol group, and these effects were dose-dependent The findings suggested resveratrol treatment in an animal model of osteoarthritis induced by D-galactose improved their weight, bone turnover markers (ALP and OC), and histological parameters were dependent on resveratrol levels.

2D MXene Nanosheets with ROS Scavenging Ability Effectively Delay Osteoarthritis Progression.

MXenes nanosheets with high conductivity, hydrophilicity, and excellent reactive oxygen species (ROS) scavenging ability have shown promise in treating various degenerative diseases correlated with abnormal ROS accumulation. Herein, the therapeutic potential of Ti3C2Tx nanosheets, which is the most widely investigated MXene material, in delaying osteoarthritis (OA) progression is demonstrated. In vitro experiments indicate the strong ROS scavenging capacity of Ti3C2Tx nanosheets and their acceptable biocompatibility. Ti3C2Tx nanosheets effectively protect chondrocytes from cell death induced by oxidative stress. In addition, Ti3C2Tx nanosheets demonstrate a prominent anti-inflammatory effect and the ability to restore homeostasis between anabolic activities and catabolic activities in chondrocytes. Furthermore, RNA sequencing reveals the potential mechanism underlying the Ti3C2Tx nanosheet-mediated therapeutic effect. Finally, the in vivo curative effect of Ti3C2Tx nanosheets is verified using a rat OA model. Histological staining and immunohistochemical analyses indicate that Ti3C2Tx nanosheets effectively ameliorate OA progression. Conclusively, the in vitro and in vivo experiments suggest that Ti3C2Tx nanosheets could be a promising and effective option for OA treatment.

Modulation of chondroprotective hyaluronic acid and poloxamer gel with Ketoprofen loaded transethosomes: Quality by design-based optimization, characterization, and preclinical investigations in osteoarthritis

Osteoarthritis (OA) is a chronic joint disease that results in biomechanical and morphological changes that contribute to cartilage degradation. Ketoprofen (KP), used in the treatment of OA, is a selective inhibitor of cyclooxygenase-2 (COX-2). Topical administration of KP bypasses gastric irritation as well as first-pass metabolism and increases localized delivery. The research intricates fabrication and optimization of KP-loaded transethosomes (KP-TEs) via Taguchi orthogonal array design and Central composite design (CCD). The optimized KP-TEs depicted an average vesicle size of 110.0 ± 1.70 nm, poly dispersibility index (PDI) of 0.103 ± 0.01, zeta potential −6.08 ± 0.27 mV, and conductivity of 0.049 ± 0.0001 mS/cm. The optimized KP-TEs were loaded in composite hyaluronic acid (HA) and poloxamer 407 (Px407) for an improvement of osteotrophic and chondroprotective transethosomal gel. The drug content of KP-TEs-HA/Px407 gel was found to be 90.08 ± 1.25 %. Preclinical research has been carried out by using the monosodium iodoacetate to develop model for osteoarthritis in male wistar rats. The X-ray imaging of KP-TEs-HA/Px407 gel treated group showed intact meniscus, healthy articular joint, and normal synovial lining same as the healthy control group. The IL − 1β IL-6, IL-22, TNF-α, and IL-10, levels, X-ray imaging, and studies on histopathology demonstrated the effectiveness of transethosomal gel in reducing pain and inflammation.

Comparative transcriptomic analysis of articular cartilage of post-traumatic osteoarthritis models.

Animal models of post-traumatic osteoarthritis (PTOA) recapitulate the pathological changes observed in human PTOA. Here, skeletally mature C57Bl6 mice were subjected to either rapid-onset non-surgical mechanical rupture of the anterior cruciate ligament (ACL) or to surgical destabilisation of the medial meniscus (DMM). Transcriptome profiling of micro-dissected cartilage at day7 or day42 following ACL or DMM procedure, respectively, showed that the two models were comparable and highly correlative. Gene ontology (GO) enrichment analysis identified similarly enriched pathways that were overrepresented by anabolic terms. To address the transcriptome changes more completely in the ACL model, we also performed small RNA sequencing, describing the first microRNA profile of this model. miR-199-5p was amongst the most abundant, yet differentially expressed, microRNAs, and its inhibition in primary human chondrocytes led to a transcriptome response that was comparable to that observed in both human 'OA damaged vs intact cartilage' and murine DMM cartilage datasets. We also experimentally verified CELSR1, GIT1, ECE1 and SOS2 as novel miR-199-5p targets. Together, these data support the use of the ACL rupture model as a non-invasive companion to the DMM model.

Decreased histone H3K9 dimethylation in synergy with DNA demethylation of Spi-1 binding site contributes to ADAMTS-5 expression in articular cartilage of osteoarthritis mice.

Osteoarthritis (OA) is defined by articular cartilage degeneration, synovial membrane inflammation, and abnormal bone remodeling. Recent study has discovered that OA development is linked to an aberrant epigenetic modification of OA-related genes. Our previous research showed that DNA demethylation in ADAMTS-5 promoter region had a substantial impact on ADAMTS-5 expression in the mouse OA model. This process facilitated the binding of Spi-1 to ADAMTS-5 promoter. While alterations in histone methylation have been documented during embryonic development and cancer development, there is a paucity of data on the change in OA pathogenesis. Even no data have been reported on the role of histone modifications in ADAMTS-5 activation in OA. Following our previous study on the role of DNA methylation, we aimed to examine the contribution of histone H3K9 dimethylation in ADAMTS-5 activation in OA. Additionally, we aimed to elucidate the molecular mechanisms underlying the cooperative interaction between DNA methylation and histone H3K9 dimethylation. The potential for anti-OA intervention therapy which is based on modulating histone H3K9 dimethylation is also explored. We demonstrated that a reduction in histone H3K9 dimethylation, along with DNA demethylation of the Spi-1 binding site, had a role in ADAMTS-5 activation in the articular cartilage of OA mice. Significantly, the conditional deletion of histone demethylase to be identified as lysine-specific demethylase 1 (LSD1) in articular cartilage could alleviate the degenerative features of OA mice. Our study demonstrates the direct impact of histone H3K9 dimethylation on gene expression, which in turn contributes to OA development. This research enhances our understanding of the underlying causes of OA.

Vortioxetine reduces the development of pain‐related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down‐regulation

AbstractBackground and PurposeVortioxetine, a multimodal‐acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference.Experimental ApproachIn the monoiodoacetate (MIA)‐induced rat model of knee OA, pain‐related behaviour was assessed in weight‐bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain‐related mediators (Ngf, Il‐1β, Tnf‐α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol.Key ResultsVortioxetine and duloxetine dose dependently reduced weight‐bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA‐injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA‐injected knees to the level in sham‐injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain‐related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up‐regulated in MIA‐injected rats. This effect was male‐specific.Conclusion and ImplicationsVortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain‐related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex‐specific pattern.

Deapi-platycodin D3 attenuates osteoarthritis development via suppression of PTP1B.

Dysregulated chondrocyte metabolism is an essential risk factor for osteoarthritis (OA) progression. Maintaining cartilage homeostasis represents a promising therapeutic strategy for the treatment of OA. However, no effective disease-modifying therapy is currently available to OA patients. To discover potential novel drugs for OA, we screened a small-molecule natural product drug library and identified deapi-platycodin D3 (D-PDD3), which was subsequently tested for its effect on extracellular matrix (ECM) properties and on OA progression. We found that D-PDD3 promoted the generation of ECM components in cultured chondrocytes and cartilage explants and that intra-articular injection of D-PDD3 delayed disease progression in a trauma-induced mouse model of OA. To uncover the underlying molecular mechanisms supporting these observed functions of D-PDD3, we explored the targets of D-PDD3 via screening approach integrating surface plasmon resonance with liquid chromatography-tandem mass spectrometry. The results suggested that D-PDD3 targeted tyrosine-protein phosphatase non-receptor type 1 (PTP1B), deletion of which restored chondrocyte homeostasis and markedly attenuated destabilization of the medial meniscus induced OA. Further cellular and molecular analyses showed that D-PDD3 maintained cartilage homeostasis by directly binding to PTP1B and consequently suppressing the PKM2/AMPK pathway. These findings demonstrated that D-PDD3 was a potential therapeutic drug for the treatment of OA and that PTP1B served as a protein target for the development of drugs to treat OA. This study provided significant insights into the development of therapeutics for OA treatment, which, in turn, helped to improve the quality of life of OA patients and to reduce the health and economic burden.

Ginkgolide A enhances FoxO1 expression and reduces endoplasmic reticulum stress to mitigate osteoarthritis in mice

This study aimed to investigate the effects of Ginkgolide A (GA) on chondrocytes under oxidative stress and to elucidate its potential molecular mechanisms. Using a destabilization of the medial meniscus (DMM) model in mice and an in vitro osteoarthritis (OA) model induced by tert-butyl hydroperoxide (TBHP) in chondrocytes, we validated the therapeutic efficacy and underlying mechanisms of GA. Potential OA targets of GA were identified through network pharmacology, Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Further exploration into the effects on endoplasmic reticulum stress (ERS), apoptosis, extracellular matrix (ECM) degradation, and Forkhead Box O1 (FoxO1) related pathways was conducted using Western blotting, immunofluorescence, TUNEL staining, flow cytometry, X-ray, micro-computed tomography (Micro-CT) analysis, and histological staining. The results demonstrated that GA upregulated FoxO1 expression and inhibited ERS-related signaling pathways, thereby reducing apoptosis and ECM degradation. In conclusion, GA significantly alleviated OA symptoms both in vitro and in vivo, suggesting its potential as a therapeutic agent for OA.

Lesion-localized hydrogels functionalized with engineered extracellular matrix restore cellular homeostasis by enhancing mitochondrial energy metabolism for osteoarthritis therapy

Cartilage damage and degeneration are fundamental pathological features of osteoarthritis (OA), attributed largely to disruptions in chondrocyte homeostasis. Tissue engineering employing functional bioactive materials presents a promising avenue for cartilage regeneration and repair. Particularly, extracellular matrix (ECM) produced by mesenchymal stem cells (MSCs) is gaining traction in the field of tissue engineering and scaffold-based regenerative therapies due to its robust bioactivity and excellent biocompatibility. In this study, we utilized specific inflammatory cytokines associated with OA as stimulators to optimize the MSC-derived secretome. Our in vitro experiments demonstrated that the engineered ECM effectively inhibited early chondrocyte apoptosis, reversed cellular senescence, and maintained anabolic-catabolic equilibrium. Moreover, we developed aldehyde- and methacrylic anhydride-modified hyaluronic acid hydrogels incorporated with ECM (ECM@AH) using photo-cross-linking techniques. The affinity of these ECM-functionalized hydrogels for degraded cartilage was confirmed through in situ cartilage lesion localization experiments in the knee joints of rat OA models. Further in vitro analysis revealed that the engineered ECM@AH, especially IFN-γ-ECM@AH, sustains chondrocyte homeostasis by restoring mitochondrial energy metabolism. Animal studies demonstrated that ECM@AH, localized to cartilage lesions, could reverse cartilage matrix degradation and promote cartilage repair, underscoring the potential of this biomaterial in OA treatment.

Supramolecular nanoparticle loaded with bilirubin enhances cartilage protection and alleviates osteoarthritis via modulating oxidative stress and inflammatory responses

Osteoarthritis (OA) is a chronic inflammation that gradually leads to cartilage degradation. Prolonged chondrocyte oxidative stress contributes to the development of diseases, including chondrocyte apoptosis, cartilage matrix degradation, and aggravation of articular cartilage damage. Bilirubin (BR) possesses strong antioxidant properties by scavenging reactive oxygen species (ROS) and potent protection effects against inflammation. However, its insolubility and short half-life limit its clinical use. Therefore, we developed a supramolecular system of ε-polylysine (EPL) conjugated by β-cyclodextrin (β-CD) on the side chain, and bilirubin was loaded via host-guest interactions, which resulted in the self-assemble of this system into bilirubin-loaded polylysine-β-cyclodextrin nanoparticle (PB) with improving solubility while reducing toxicity and prolonging medication action time. To explore PB's potential pharmacological mechanisms on OA, we established in vitro and in vivo OA models. PB exerted ROS-scavenging proficiency and anti-apoptotic effects on rat chondrocytes by activating the Nrf2-HO-1/GPX4 signaling pathway. Additionally, PB reprogrammed the cartilage microenvironment by regulating the NF-κB signaling pathway to maintain chondrocyte function. Animal experiments further confirmed that PB had excellent scavenging ability for ROS and inflammatory factors related to charge adsorption with cartilage as well as long retention ability. Together, this work suggests that PB has superior protective abilities with beneficial effects on OA, indicating its great potential for intervention therapy targeting chondrocytes.

Osteoarthritis induced by monosodium iodoacetate model

Objectives: this study aimed to highlight the evolution of the osteoarthritis (OA) model induced by monosodium iodoacetate (MIA) and its collaboration with the knowledge of the pathophysiology of inflammation, hypernociception and cartilage degeneration. Methods: PubMed and Science Direct were used with the descriptors: knee osteoarthritis or osteoarthritis of ankle) and (rat or osteoarthritis induced by monoiodoacetate) and (animal model of osteoarthritis or joint nociception). Studies containing rats, mice, and monoiodoacetate-induced osteoathritis were included. Exclusion criteria were: Animal models of osteoarthritis induced by destabilization; meniscectomy-induced osteoarthritis; non-invasive animal models of osteoarthritis induced by fracture, compression and tibial overload; animal models of osteoarthritis with large animals and models of osteoarthritis by papain or bacterial collagenase. We summarized studies that used MIA to induce knee or ankle OA in rats or mice and the evolution of the inflammatory markers. Results: a total of 38 original manuscripts met the inclusion criteria and were considered in the study. The model of OA induced by MIA is well-established and explored with several methodologies and has been widely used in different species. MIA induces cell death, progressive loss of chondrocytes and histological changes that mimics human OA. Studies with this model demonstrated inflammation, neurogenic hyperalgesia, release of cytokines and matrix metalloproteinases. More recently, molecular biology data confirm the activation of nuclear transcription factors, which modulates the expression of citokines in apoptotic chondrocytes. Conclusion: the MIA-induced OA has been useful in predicting several characteristics for the elucidation of osteoarthritis pathophysiology.

Machine learning algorithm-based biomarker exploration and validation of mitochondria-related diagnostic genes in osteoarthritis.

The role of mitochondria in the pathogenesis of osteoarthritis (OA) is significant. In this study, we aimed to identify diagnostic signature genes associated with OA from a set of mitochondria-related genes (MRGs). First, the gene expression profiles of OA cartilage GSE114007 and GSE57218 were obtained from the Gene Expression Omnibus. And the limma method was used to detect differentially expressed genes (DEGs). Second, the biological functions of the DEGs in OA were investigated using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Wayne plots were employed to visualize the differentially expressed mitochondrial genes (MDEGs) in OA. Subsequently, the LASSO and SVM-RFE algorithms were employed to elucidate potential OA signature genes within the set of MDEGs. As a result, GRPEL and MTFP1 were identified as signature genes. Notably, GRPEL1 exhibited low expression levels in OA samples from both experimental and test group datasets, demonstrating high diagnostic efficacy. Furthermore, RT-qPCR analysis confirmed the reduced expression of Grpel1 in an in vitro OA model. Lastly, ssGSEA analysis revealed alterations in the infiltration abundance of several immune cells in OA cartilage tissue, which exhibited correlation with GRPEL1 expression. Altogether, this study has revealed that GRPEL1 functions as a novel and significant diagnostic indicator for OA by employing two machine learning methodologies. Furthermore, these findings provide fresh perspectives on potential targeted therapeutic interventions in the future.

Thioredoxin-Interacting Protein's Role in NLRP3 Activation and Osteoarthritis Pathogenesis by Pyroptosis Pathway: In Vivo Study.

Thioredoxin-interacting protein (TXNIP) has been involved in oxidative stress and activation of the NOD-like receptor protein-3 (NLRP3) inflammasome, directly linking it to the pyroptosis pathway. Furthermore, pyroptosis may contribute to the inflammatory process in osteoarthritis (OA). The purpose of this study was to investigate the role of TXNIP in activating the NLRP3 inflammasome through the pyroptosis pathway in an OA rat model. Destabilization of the medial meniscus (DMM) was induced in the OA model with intra-articular injections of adeno-associated virus (AAV) overexpressing (OE) or knocking down (KD) TXNIP. A total of 48 healthy rats were randomly divided into six groups (N = 8 each). During the experiment, the rats' weights, mechanical pain thresholds, and thermal pain thresholds were measured weekly. Morphology staining, micro-CT, 3D imaging, and immunofluorescence (IF) staining were used to measure the expression level of TXNIP, and ELISA techniques were employed. OE-TXNIP-AAV in DMM rats aggravated cartilage destruction and subchondral bone loss, whereas KD-TXNIP slowed the progression of OA. The histological results showed that DMM modeling and OE-TXNIP-AAV intra-articular injection caused joint structure destruction, decreased anabolic protein expression, and increased catabolic protein expression and pyroptosis markers. Conversely, KD-TXNIP-AAV slowed joint degeneration. OE-TXNIP-AVV worsened OA by accelerating joint degeneration and damage, while KD-TXNIP-AAV treatment had a protective effect.

A novel Osteoarthritis scoring system to separate typical OA joint degeneration from non-typical lesions in male Sprague Dawley rats

ObjectiveTo develop a novel scoring system to characterize osteoarthritis-related degeneration distinct from spontaneous subchondral bone lesions observed in the tibia and femur of male Sprague Dawley rats. MethodKnee joints from male rats following 12 weeks of a diet-induced obesity model of osteoarthritis (OA) were assessed. OA histopathological changes (OAHC) were assessed in the knee joints. All scores were evaluated using a modified Mankin score and a modified Osteoarthritis Research Society International histological score. OAHC were divided into 3 categories: (I) Typical OA score evaluating the changes in cartilage structure, cellularity, proteoglycan depletion, and tidemark integrity, (II) A novel Non-typical OA score evaluating cartilage integrity, and the size of local thickening, fragmentation and degeneration along the tidemark and the size and severity of the subchondral bone lesion, and (III) Total OA score comprised of both, the Typical and the Non-typical scores. ResultsRats exposed to a high fat/high sucrose diet had higher Typical OA score compared to a control group (Chow). Non-typical and Total OA scores revealed no differences in the severity of the lesions between the HFS and the Chow group animals. All scoring systems had excellent intra- and inter-examiner reliability. ConclusionThe spontaneous bone lesions observed in male Sprague Dawley rats can obscure the effect of the diet-induced obesity if the classical scoring system is used to assess joint degeneration. The newly proposed scoring method provides a reliable method to distinguish classical OA joint degeneration from spontaneous Non-typical lesions occurring in these rats.