Progression Of Cartilage Degeneration Research Articles

Effect of striped catfish (Pangasianodon hypophthalmus) for cartilage thickness and chondrocyte count in mice (Mus musculus)

Osteoarthritis (OA) is a leading cause of disability worldwide, characterized by progressive cartilage degeneration. Nutritional interventions, particularly omega-3 polyunsaturated fatty acids (PUFAs), have shown potential in slowing cartilage degradation. Striped catfish (Pangasianodon hypophthalmus) is a rich source of omega-3 PUFAs and essential amino acids, which may support cartilage health and regeneration. A post-test-only control group design was implemented using 50 male mice (Mus musculus), randomly assigned to either a control group (standard diet) or a treatment group (striped catfish-supplemented diet). The intervention lasted for eight weeks. Cartilage thickness and chondrocyte count were measured histologically using ImageJ software, and statistical significance was determined using independent t-tests and Mann-Whitney U tests. The treatment group exhibited significantly increased cartilage thickness (p < 0.001) and chondrocyte count (p < 0.001) compared to controls. These findings suggest that the nutrients in striped catfish enhance cartilage metabolism, reduce inflammation, and support extracellular matrix (ECM) integrity. Striped catfish supplementation demonstrates significant benefits for cartilage health, potentially aiding in OA management. Future research should explore optimal dosages and long-term effects to further validate these findings.

Three-dimensional cell culture-derived extracellular vesicles loaded alginate/hyaluronic acid composite scaffold as an optimal therapy for cartilage defect regeneration.

Osteoarthritis (OA) is a chronic musculoskeletal disease characterized by joint inflammation and progressive degeneration of articular cartilage. Currently a definitive cure for OA remains to be a challenge due to the very low self-repair capacity of cartilage, thus development of more effective therapies is needed for cartilage repair. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great potential as therapeutic agents for stimulating regeneration of articular cartilage. However, a standardized protocol is still lacking for manufacturing of highly active EVs for clinical applications. This study aimed to investigate the efficient production of highly active EVs by 3-dimensional (3D) MSC culture, verify the reparative efficacy of EVs on cartilage defect and elucidate the repair mechanisms. Umbilical cord MSCs were embedded in alginate to form MSC spheroids for 3D culture in human platelet lysate (hPL)-containing medium, which produced 3D culture-derived EVs (3D-EVs) with a significantly improved yield. The 3D-EVs expressed higher level of VEGF, and appeared superior to 2D monolayer MSC culture-derived EVs (2D-EVs) to improve migration and proliferation in MSCs and inflammatory chondrocytes, and to suppress expression of cartilage-degrading factors. Importantly, the 3D-EVs and sodium alginate (SA)-hyaluronic acid (HA) composite hydrogel (3D-EVs/SA-HA) demonstrated significantly improved therapeutic efficacy than 2D-EVs/ SA-HA hydrogel for repair of cartilage defect in vivo. The underlying mechanisms are associated with the concomitant upregulation of type II collagen and cartilage synthesis and downregulation of MMP13 in cartilage tissues. Collectively, these data showed that highly active MSC EVs could be efficiently manufactured by 3D cell culture with hPL-containing medium, and these EVs were superior to 2D-EVs for the repair of articular cartilage defect.

Promising LOX proteins for cartilage-targeting osteoarthritis therapy.

Osteoarthritis (OA) is the most affected joint disease worldwide, touching millions of people every year. It is caused by a progressive degeneration of articular cartilage, causing pain and limited mobility. Among the pathways involved in cartilage homeostasis, "LOX" proteins (referring to three distinct protein families, very often confused in the literature) play a prominent role. The lipoxygenase enzyme family is involved in the inflammatory process of OA by inducing the production of several pro-inflammatory leukotrienes. Lectin-like oxidized low-density lipoprotein family are receptors located at the surface of chondrocytes, which interact with their ligand, ox-LDL, activating several catabolic pathways involved in OA pathophysiology. Finally, lysyl oxidase and lysyl oxidase-like are enzymes expressed intracellularly (in chondrocytes' cytoplasm) involved in elastin biosynthesis and collagen cross-linking in cartilage extracellular matrix. EMA and FDA have not yet approved any drug targeting the LOX proteins. In particular, today lysyl oxidase-like 2 is considered as a new promising target for OA modifying therapy. This review clarifies the main roles of different LOX proteins involved in the progression of OA. Potential LOX inhibitoion strategies for drug development in advanced OA therapy, particularly for local intraarticular delivery, were listed and discussed for each target type. This review, therefore, proposes promising strategies for future drug development in OA treatment.

Charge‐Guided Cartilage‐Penetrating Micro/Nanocarriers That Inhibit Piezo1 and Protect Cartilage to Alleviate Osteoarthritis

AbstractOsteoarthritis (OA), characterized by progressive cartilage degeneration and chronic joint pain, represents a major global health challenge. While intra‐articular drug delivery is a common therapeutic approach, its efficacy is limited by poor drug penetration through the dense cartilage matrix, particularly for hydrophobic compounds. Here, a novel charge‐guided micro/nanocarrier system designed to overcome these delivery challenges is presented. By modifying amylose with glycidyl trimethyl ammonium chloride (GTAC), it is developed positively charged carriers that demonstrate enhanced penetration into the negatively charged cartilage matrix. The hydrophobic Piezo1 inhibitor, Margaric acid (MA), is efficiently encapsulated within the helical cavity of modified amylose through DMSO‐ultrasound treatment, creating Cationic Amylose Micro/Nanocarriers@MA (CAMNC@MA). This system effectively delivers MA to chondrocytes, where Piezo1, a crucial mechanosensor implicated in OA development, can be precisely modulated. These results demonstrate that CAMNC@MA successfully inhibits abnormal mechanical force‐induced Piezo1 activation in chondrocytes, enhances cell survival, reduces matrix degradation, and effectively alleviates OA progression. This innovative drug delivery platform offers a promising strategy for clinical OA treatment by combining enhanced matrix penetration with efficient matrix penetration of hydrophobic therapeutic agents.

Integrated analysis of bioinformatics, mendelian randomization, and experimental validation reveals novel diagnostic and therapeutic targets for osteoarthritis: progesterone as a potential therapeutic agent

BackgroundOsteoarthritis (OA), characterized by progressive degeneration of cartilage and reactive proliferation of subchondral bone, stands as a prevalent condition in orthopedic clinics. However, the precise mechanisms underlying OA pathogenesis remain inadequately explored.MethodsIn this study, Random Forest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) machine learning techniques were employed to identify hub genes. Based on these hub genes, an Artificial Neural Network (ANN) diagnostic model was constructed. The Drug Signatures Database (DSigDB) was utilized to screen small-molecule drugs targeting these hub genes, and molecular docking analyses and molecular dynamics simulations were employed to explore and validate the binding interactions between proteins and small-molecule drugs. Expression changes of the hub genes under inflammatory conditions were validated through in vitro experiments, including RT-qPCR and Western blotting, and the therapeutic effects of the identified small-molecule drug on chondrocytes under inflammatory conditions were further verified in vitro. Lastly, Mendelian randomization analysis was conducted to examine the causal association between progesterone levels and various OA phenotypes.ResultsIn this study, we identified three hub genes: interleukin 1 receptor-associated kinase 3 (IRAK3), integrin subunit beta-like 1 (ITGBL1), and Ras homolog family member U (RHOU). An Artificial Neural Network (ANN) diagnostic model constructed based on these hub genes demonstrated excellent performance in both training and validation phases. Screening with the Drug Signatures Database (DSigDB) identified progesterone as a small-molecule drug targeting these key proteins. Molecular docking analysis using AutoDock Vina revealed that progesterone exhibited binding energies of ≤ -7 kcal/mol with each of the key proteins, indicating strong binding affinity. Furthermore, molecular dynamics simulations validated the stability and strength of these interactions. RT-qPCR and Western blotting confirmed the downregulation of the hub genes in IL-1β-treated chondrocytes. Western blotting also demonstrated the potential therapeutic effects of progesterone on IL-1β-treated chondrocytes. Finally, Mendelian randomization analysis established a significant association between progesterone levels and multiple OA phenotypes.ConclusionIn our study, IRAK3, ITGBL1, and RHOU were identified as potential novel diagnostic and therapeutic targets for OA. Progesterone was preliminarily validated as a small-molecule drug with potential effects on OA. Further research is crucial to elucidate the pathogenesis of OA and the specific therapeutic mechanisms involved.

Interaction Between YTH Domain-Containing Family Protein 2 and SET Domain-Containing Lysine Methyltransferase 7 Suppresses Autophagy in Osteoarthritis Chondrocytes, Exacerbating Cartilage Damage.

Osteoarthritis (OA) is characterized by progressive cartilage degeneration mediated by various molecular pathways, including inflammatory and autophagic processes. SET domain-containing lysine methyltransferase 7 (SETD7), a methyltransferase, has been implicated in OA pathology. This study investigates the expression pattern of SETD7 in OA and its role in promoting interleukin-1 beta (IL-1β)-induced chondrocyte injury through modulation of autophagy and inflammation. The expression of SETD7 in cartilage tissues from OA patients and healthy controls was quantified using quantitative reverse transcription PCR and Western blot analysis. Small interfering RNA targeting SETD7 (si-SETD7) was transfected into human articular chondrocytes (HACs) treated with IL-1β to examine its impact on cellular viability, apoptosis, inflammatory responses, and autophagy. Functional assays including Cell Counting Kit-8, flow cytometry, enzyme-linked immunosorbent assay, and commercial kits were employed to assess biochemical changes. Interaction between YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) and SETD7 was explored using RNA immunoprecipitation and co-immunoprecipitation assays. SETD7 was overexpressed in OA cartilage compared with controls and increased further upon IL-1β treatment. Knockdown of SETD7 in IL-1β-treated HACs improved cellular viability, decreased apoptosis, and reversed the adverse effects on lactate dehydrogenase release and inflammatory markers (tumor necrosis factor-alpha and interleukin-6) while enhancing antioxidant enzymes (catalase, malondialdehyde, and superoxide dismutase). Additionally, autophagy was restored, as evidenced by changes in the levels of autophagy related 5, Beclin1, and sequestosome 1. Interfering with autophagy using chloroquine negated the protective effects of SETD7 knockdown. Furthermore, YTHDF2 was found to stabilize SETD7 mRNA, influencing its expression and enhancing IL-1β-induced chondrocyte injury. SETD7 plays a critical role in the pathogenesis of OA by modulating chondrocyte survival, apoptosis, inflammation, and autophagy. The interaction between YTHDF2 and SETD7 exacerbates chondrocyte injury under inflammatory conditions, highlighting potential therapeutic targets for OA treatment. The YTHDF2/SETD7 axis offers a novel insight into the molecular mechanisms governing cartilage degeneration in OA.

Innovative Approaches in Knee Osteoarthritis Treatment: A Comprehensive Review of Bone Marrow-Derived Products.

Knee osteoarthritis (OA) is a chronic articular disease characterized by the progressive degeneration of cartilage and bone tissue, leading to the appearance of subchondral cysts, osteophyte formation, and synovial inflammation. Conventional treatments consist of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, and glucocorticoids. However, the prolonged use of these drugs causes adverse effects. NSAIDs, for instance, are known to be nephrotoxic, increasing the damage to articular cartilage. New therapies capable of accelerating the process of tissue regeneration and repair are being discussed, such as the use of orthobiologics that are naturally found in the body and obtained through minimally invasive collection and/or laboratory manipulations. Bone marrow aspirate (BMA) and bone marrow aspirate concentrate (BMAC) are both rich in hematopoietic stem cells, mesenchymal stem cells (MSCs), and growth factors (GFs) that can be used in the healing process due to their anabolic and anti-inflammatory effects. The aim of this literature review is to assess the efficacy of BMA and BMAC in the treatment of knee OA based on the favorable results that researchers have obtained with the use of both orthobiologics envisaging an accelerated healing process and the prevention of OA progression.

Bone marrow mesenchymal stem cells (BM-MSCs) modulate MMP9 expression and promote articular cartilage regeneration in knee joint of a model of arthritis induced in adult rat: histological and immunohistochemical study.

Arthritis is characterized by the progressive degeneration of articular cartilage, and the avascular nature of cartilage limits its capacity for self-repair. Stem cells are considered a promising treatment option due to their multipotent differentiation potential. The aim of this work was to investigate the structural changes in the hyaline articular cartilage of the knee joint in a model of arthritis induced by complete Freund's adjuvant, and to assess intra-articular injection of bone marrow mesenchymal stem cells (BM-MSCs) through both histological and immunohistochemical study. Adult male albino rats were divided into four groups: group 0 (donor group), group I (control group), group II (arthritis group) and group III (BM-MSCs treated arthritis group). Samples were collected 2, 6 and 10weeks after the onset of the experiment. Sections were stained with; hematoxylin and eosin, Safranin O fast green stain, Masson's trichrome stain and anti-MMP9 antibody. In Group II (arthritis group), the articular cartilage showed signs of degeneration, including chondrocyte extensive proliferation, fibrillations, fissuring, and denudation, with fibrous tissue covering the exposed surface. There was a significant decrease in cartilage thickness, collagen content, and proteoglycan levels. The integrated density of MMP9 in the cartilage was significantly increased compared to Group I (control group). In contrast, Group III (BM-MSCs-treated arthritis group) exhibited a continuous cartilage surface with no cracks or fissures. There was a significant increase in cartilage thickness, collagen content, and proteoglycan levels, while the integrated density of MMP9 was significantly decreased compared to Group II (arthritis group).

Exploring the role of ATF3 and ferroptosis-related RNA expression in osteoarthritis: An RNA analysis approach to immune infiltration.

Osteoarthritis (OA) is a widespread joint disorder that is primarily noted for the progressive degeneration of joint cartilage, accompanied by a significant inflammatory response. Recently, there has been a growing interest in understanding the roles of ATF3 and ferritin-related RNAs in the context of immune responses and inflammatory processes. However, their specific functions and mechanisms in the progression of osteoarthritis have remained largely ambiguous and underexplored. The primary objective of this study was to thoroughly investigate the changes in expression levels of ATF3 and ferritin-related RNAs within osteoarthritic tissues, as well as to examine their potential effects on immune cell infiltration. To achieve this, advanced RNA sequencing technology was employed to meticulously analyze the expression levels of ATF3 and the ferritin-related RNAs. Furthermore, bioinformatics methods were utilized to assess the infiltration patterns of various immune cells and to explore the correlation between these infiltration patterns and the expression levels of RNA. The findings from this study revealed that both ATF3 and ferritin-related RNAs exhibited significantly elevated expression levels in tissues affected by osteoarthritis. Additionally, the immunoinfiltration analysis highlighted a positive correlation between the degree of infiltration of T cells and macrophages and the levels of ferritin-related RNAs. Such findings suggest that the presence of these immune cells is intricately linked to the expression of ferritin-associated RNAs. Further investigations indicated that ferritin-associated RNAs play a critical role in the progression of osteoarthritis by modulating inflammatory responses and influencing the activity of various immune cells. Consequently, both ATF3 and ferritin-related RNAs demonstrate abnormal expression patterns in osteoarthritis, which are closely associated with the infiltration of immune cells.

Ruscogenin attenuates osteoarthritis by modulating oxidative stress-mediated macrophage reprogramming via directly targeting Sirt3

BackgroundSynovial inflammation, Cartilage erosion, and subchondral osteosclerosis, which are collectively referred to as the triad of pathogenesis, contribute to osteoarthritis (OA) progression. Specifically, the M1 macrophage in the synovium worsens the development of the illness and is a significant factor in the deterioration and functioning of cartilage. ObjectiveTo investigate whether Ruscogenin attenuates progressive degeneration of articular cartilage in rats with anterior cruciate ligament transection (ACLT)-induced osteoarthritis (OA) by modulating macrophage reprogramming and to explore its specific mechanism of action. MethodsIn vitro, SW1353 cells and RAW264.7 cells were applied to elucidate the mechanisms by which Ruscogenin protects articular cartilage. Specifically, the expression levels of molecules related to cartilage ECM synthesis and degradation enzymes and macrophages were analysed. In vivo, a rat osteoarthritis model was established using ACLT. The protective effect of Ruscogenin on articular cartilage was observed. ResultsRuscogenin significantly reversed LPS-induced macrophage inflammatory response and promoted cartilage regeneration-related factors. In addition, Ruscogenin had a significant protective effect on the knee joint of ACLT rats, effectively preventing cartilage degeneration. These positive therapeutic effects were achieved on the one hand by Ruscogenin regulating macrophage reprogramming by targeting Sirt3, and on the other hand Ruscogenin could attenuate the ROS level of chondrocytes thereby inhibiting chondrocyte ferroptosis. ConclusionsRuscogenin exerts chondroprotective effects by regulating macrophage reprogramming and inhibiting chondrocyte ferroptosis.

Injectable hydrogel encapsulating siMMP13 with anti-ROS and anti-apoptotic functions for osteoarthritis treatment

BackgroundOsteoarthritis (OA) is a degenerative joint disease characterized by the progressive degeneration of articular cartilage, leading to pain, stiffness, and loss of joint function. The pathogenesis of OA involves multiple factors, including increased intracellular reactive oxygen species (ROS), enhanced chondrocyte apoptosis, and disturbances in cartilage matrix metabolism. These processes contribute to the breakdown of the extracellular matrix (ECM) and the loss of cartilage integrity, ultimately resulting in joint damage and dysfunction. RNA interference (RNAi) therapy has emerged as a promising approach for the treatment of various diseases, including hATTR and acute hepatic porphyria. By harnessing the natural cellular machinery for gene silencing, RNAi allows for the specific inhibition of target genes involved in disease pathogenesis. In the context of OA, targeting key molecules such as matrix metalloproteinase-13 (MMP13), which plays a critical role in cartilage degradation, holds great therapeutic potential.ResultsIn this study, we developed an innovative therapeutic approach for OA using a combination of liposome-encapsulated siMMP13 and NG-Monomethyl-L-arginine Acetate (L-NMMA) to form an injectable hydrogel. The hydrogel served as a delivery vehicle for the siMMP13, allowing for sustained release and targeted delivery to the affected joint. Experiments conducted on destabilization of the medial meniscus (DMM) model mice demonstrated the therapeutic efficacy of this composite hydrogel. Treatment with the hydrogel significantly inhibited the degradation of cartilage matrix, as evidenced by histological analysis showing preserved cartilage structure and reduced loss of proteoglycans. Moreover, the hydrogel effectively suppressed intracellular ROS accumulation in chondrocytes, indicating its anti-oxidative properties. Furthermore, it attenuated chondrocyte apoptosis, as demonstrated by decreased levels of apoptotic markers.ConclusionIn summary, the injectable hydrogel containing siMMP13, endowed with anti-ROS and anti-apoptotic properties, may represent an effective therapeutic strategy for osteoarthritis in the future.

Targeting RIP3 inhibits osteoarthritis development by restoring anabolic-catabolic balance in the bone-cartilage unit

BackgroundOsteoarthritis (OA) is a debilitating joint disorder characterized by progressive cartilage degeneration. During OA, subchondral bone undergoes microstructural and molecular changes that precede cartilage degradation. However, specific mechanisms underlying metabolic dysregulation of the bone-cartilage unit remain unclear. This study aims to investigate the role of receptor-interacting protein kinase-3 (RIP3) in OA progression, focusing on bone-cartilage metabolic homeostasis. MethodsRIP3-mediated pathological and metabolic alterations in chondrocytes, osteoblasts, and bone marrow-derived macrophages (BMMs) were evaluated. RIP3-mediated OA manifestations in cartilage and, more importantly, subchondral bone were determined by intra-articular overexpression of RIP3 in rats. The protective effect of RIP3 deficiency on the bone-cartilage unit during OA was systematically investigated using Rip3 knockout mice. The CMap database was used to screen for compounds that abrogate RIP3-induced OA pathological changes. ResultsRIP3 was upregulated in the cartilage and subchondral bone of OA patients and post-traumatic OA mouse model. RIP3 overexpression not only inhibited extracellular matrix (ECM) anabolism in chondrocytes but also attenuated osteoblast differentiation, whereas RIP3 deficiency blunted receptor activator of NF-kappaB ligand-mediated osteoclastogenesis of BMMs. Intra-articular RIP3 overexpression induced the imbalance of SP7+ osteoblasts/tartrate-resistant acid phosphatase (TRAP)+ osteoclasts within the subchondral bone in addition to cartilage degeneration in rats, while Rip3 deletion significantly improved structural outcomes of the bone-cartilage unit, and achieved pain relief as well as functional improvement in surgery-induced and spontaneous OA mouse models. Mechanistically, RIP3 initiates OA by perturbing critical events, including cartilage metabolism, inflammatory responses, senescence, and osteoclast differentiation. Clofibrate, a hypolipidemic drug, was identified as a novel RIP3 inhibitor that reverses ECM catabolism in OA. ConclusionsRIP3 is an essential governor of whole joint metabolic homeostasis by regulating both cartilage metabolism and subchondral bone remodeling. Reconstruction of the bone-cartilage unit by targeting RIP3 might provide a two-birds-one-stone approach for the development of future OA therapies.

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.

Identification of ion channel-related genes as diagnostic markers and potential therapeutic targets for osteoarthritis through bioinformatics and machine learning-based approaches

Background Osteoarthritis (OA) is a debilitating joint disorder characterized by the progressive degeneration of articular cartilage. Although the role of ion channels in OA pathogenesis is increasingly recognized, diagnostic markers and targeted therapies remain limited. Methods In this study, we analyzed the GSE48556 dataset to identify differentially expressed ion channel-related genes (DEGs) in OA and normal controls. We employed machine learning algorithms, least absolute shrinkage and selection operator(LASSO), and support vector machine recursive feature elimination(SVM-RFE) to select potential diagnostic markers. Then the gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to explore the potential diagnostic markers’ involvement in biological pathways. Finally, weighted gene co-expression network analysis (WGCNA) was used to identify key genes associated with OA. Results We identified a total of 47 DEGs, with the majority involved in transient receptor potential (TRP) pathways. Seven genes (CHRNA4, GABRE, HTR3B, KCNG2, KCNJ2, LRRC8C, and TRPM5) were identified as the best characteristic genes for distinguishing OA from healthy samples. We performed clustering analysis and identified two distinct subtypes of OA, C1, and C2, with differential gene expression and immune cell infiltration profiles. Then we identified three key genes (PPP1R3D, ZNF101, and LOC651309) associated with OA. We constructed a prediction model using these genes and validated it using the GSE46750 dataset, demonstrating reasonable accuracy and specificity. Conclusions Our findings provide novel insights into the role of ion channel-related genes in OA pathogenesis and offer potential diagnostic markers and therapeutic targets for the treatment of OA.

Bergamottin (Ber) ameliorates the progression of osteoarthritis via the Sirt1/NF-κB pathway.

Osteoarthritis (OA) is a common chronic disease characterized by progressive cartilage degeneration and secondary synovial inflammation. Bergamottin (Ber) is an important natural derivative of the furanocoumarin compound, extracted from natural foods, such as the pulp of grapefruits and pomelos. Ber exhibits several characteristicsthat are beneficial to human health, such as anti-inflammation, antioxidant, and anti-cancer effects. However, the role of Ber in the treatment of OA has not been elucidated to date. Therefore, in the present study, in vitro experiments were conducted, which demonstrated that Ber reduces the secretion of inducible nitric oxide synthase (iNOS), nitric oxide (NO), cyclooxygenase-2 (COX2), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin E2 (PGE2) under the stimulation of interleukin-1β (IL-1β). Ber also reversed the IL-1 β-mediated aggrecan and type II collagen degradation within the extracellular matrix (ECM). In addition, in vivo experiments were conducted, in which Ber ameliorated the progression of OA in mice. It was revealed that Ber exerted its cellular effect by activating the Sirt1/NF-kB pathways. In conclusion, the present study demonstrated the therapeutic potential of Ber in the context of OA.

Intra-Articular Injection of PLGA/Polydopamine Core-Shell Nanoparticle Attenuates Osteoarthritis Progression.

Osteoarthritis (OA) is a common joint disease characterized by progressive cartilage degeneration. Unfortunately, currently available clinical drugs are mainly analgesics and cannot alleviate the development of OA. Kartogenin (KGN) has been found to promote the differentiation of bone marrow mesenchymal stem cells (BMSCs) into chondrocytes for the treatment of cartilage damage in early OA. However, KGN, as a small hydrophobic molecule, is rapidly cleared from the synovial fluid after intra-articular injection. This study synthesized a KGN-loaded nanocarrier based on PLGA/polydopamine core/shell structure to treat OA. The fluorescence signal of KGN@PLGA/PDA-PEG-E7 nanoparticles lasted for 4 weeks, ensuring long-term sustained release of KGN from a single intra-articular injection. In addition, the polyphenolic structure of PDA enables it to effectively scavenge reactive oxygen species, and the BMSC-targeting peptide E7 (EPLQLKM) endows KGN@PLGA/PDA-PEG-E7 NPs with an effective affinity for BMSCs. As a result, the KGN@PLGA/PDA-PEG-E7 nanoparticles could effectively induce cartilage in vitro and protect the cartilage and subchondral bone in a rat ACLT model. This therapeutic strategy could also be extended to the delivery of other drugs, targeting other tissues to treat joint diseases.

Molecular Mechanisms Linking Osteoarthritis and Alzheimer's Disease: Shared Pathways, Mechanisms and Breakthrough Prospects.

Alzheimer's disease (AD) is a progressive neurodegenerative disease mostly affecting the elderly population. It is characterized by cognitive decline that occurs due to impaired neurotransmission and neuronal death. Even though deposition of amyloid beta (Aβ) peptides and aggregation of hyperphosphorylated TAU have been established as major pathological hallmarks of the disease, other factors such as the interaction of genetic and environmental factors are believed to contribute to the development and progression of AD. In general, patients initially present mild forgetfulness and difficulty in forming new memories. As it progresses, there are significant impairments in problem solving, social interaction, speech and overall cognitive function of the affected individual. Osteoarthritis (OA) is the most recurrent form of arthritis and widely acknowledged as a whole-joint disease, distinguished by progressive degeneration and erosion of joint cartilage accompanying synovitis and subchondral bone changes that can prompt peripheral inflammatory responses. Also predominantly affecting the elderly, OA frequently embroils weight-bearing joints such as the knees, spine and hips leading to pains, stiffness and diminished joint mobility, which in turn significantly impacts the patient's standard of life. Both infirmities can co-occur in older adults as a result of independent factors, as multiple health conditions are common in old age. Additionally, risk factors such as genetics, lifestyle changes, age and chronic inflammation may contribute to both conditions in some individuals. Besides localized peripheral low-grade inflammation, it is notable that low-grade systemic inflammation prompted by OA can play a role in AD pathogenesis. Studies have explored relationships between systemic inflammatory-associated diseases like obesity, hypertension, dyslipidemia, diabetes mellitus and AD. Given that AD is the most common form of dementia and shares similar risk factors with OA-both being age-related and low-grade inflammatory-associated diseases, OA may indeed serve as a risk factor for AD. This work aims to review literature on molecular mechanisms linking OA and AD pathologies, and explore potential connections between these conditions alongside future prospects and innovative treatments.

Chondrocyte membrane-coated nanoparticles promote drug retention and halt cartilage damage in rat and canine osteoarthritis.

Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. A challenge in the development of disease-modifying drugs is effective delivery to chondrocytes. The unique structure of the joint promotes rapid clearance of drugs through synovial fluid, and the dense and avascular cartilage extracellular matrix (ECM) limits drug penetration. Here, we show that poly(lactide-co-glycolic acid) nanoparticles coated in chondrocyte membranes (CM-NPs) were preferentially taken up by rat chondrocytes ex vivo compared with uncoated nanoparticles. Internalization of the CM-NPs was mediated primarily by E-cadherin, clathrin-mediated endocytosis, and micropinocytosis. These CM-NPs adhered to the cartilage ECM in rat knee joints in vivo and penetrated deeply into the cartilage matrix with a residence time of more than 34 days. Simulated synovial fluid clearance studies showed that CM-NPs loaded with a Wnt pathway inhibitor, adavivint (CM-NPs-Ada), delayed the catabolic metabolism of rat and human chondrocytes and cartilage explants under inflammatory conditions. In a surgical model of rat OA, drug-loaded CM-NPs effectively restored gait, attenuated periarticular bone remodeling, and provided chondroprotection against cartilage degeneration. OA progression was also mitigated by CM-NPs-Ada in a canine model of anterior cruciate ligament transection. These results demonstrate the feasibility of using chondrocyte membrane-coated nanoparticles to improve the pharmacokinetics and efficacy of anti-OA drugs.

Electro-acupuncture modulated miR-214 expression to prevent chondrocyte apoptosis and reduce pain by targeting BAX and TRPV4 in osteoarthritis rats.

Osteoarthritis (OA) is a highly prevalent joint disorder characterized by progressive degeneration of articular cartilage, subchondral bone remodeling, osteophyte formation, synovial inflammation, and meniscal damage. Although the etiology of OA is multifactorial, pro-inflammatory processes appear to play a key role in disease pathogenesis. Previous studies indicate that electroacupuncture (EA) exerts chondroprotective, anti-inflammatory, and analgesic effects in preclinical models of OA, but the mechanisms underlying these potential therapeutic benefits remain incompletely defined. This study aimed to investigate the effects of EA on OA development in a rat model, as well as to explore associated molecular mechanisms modulated by EA treatment. Forty rats were divided into OA, EA, antagomiR-214, and control groups. Following intra-articular injection of monosodium iodoacetate to induce OA, EA and antagomiR-214 groups received daily EA stimulation at acupoints around the knee joint for 21 days. Functional pain behaviors and chondrocyte apoptosis were assessed as outcome measures. The expression of microRNA-214 (miR-214) and its downstream targets involved in apoptosis and nociception, BAX and TRPV4, were examined. Results demonstrated that EA treatment upregulated miR-214 expression in OA knee cartilage. By suppressing pro-apoptotic BAX and pro-nociceptive TRPV4, this EA-induced miR-214 upregulation ameliorated articular pain and prevented chondrocyte apoptosis. These findings suggested that miR-214 plays a key role mediating EA's therapeutic effects in OA pathophysiology, and represents a promising OA treatment target for modulation by acupuncture.

Blocking TXNIP reduced IL-1β Induced chondrocyte cell inflammation.

Osteoarthritis (OA) is the most common joint disease in the elderly and is characterized by progressive and irreversible degeneration of articular cartilage, particularly cartilage loss and callus formation. This study would like to investigate the important role and the molecular mechanism of OA progression following interleukin 1β (IL-1β)-induced chondrocyte injury regulated by TXNIP. In this study, high-purity mouse chondrocytes were obtained by enzymatic two-step digestion for primary culture. Toluidine blue staining and type II collagen immunofluorescence were used to identify cells through histochemical staining after slide mounting. The relative expression of TXNIP was detected by immunohistochemical staining and qRT-PCR.Aiming at the shRNA sequence of the TXNIP gene, the shRNA expression vector was constructed and packaged with lentivirus to form the lentiviral vector shTXNIP. After inhibiting the expression of TXNIP by transfecting shTXNIP into normal mouse chondrocytes, the CCK-8 kit was used for detecting its effect on cell proliferation after transfection, and the effect on chondrocyte apoptosis was detected by flow cytometry. The staining kit was used to detect the effect of TXNIP knockout on chondrocyte aging, and the differential expression of TNF, IL-6, MMP3, MMP13, ADAMTS-5 and type II collagen genes in chondrocytes was detected by RT-PCR and Western-bolt. Western blot was used to detect the expression of upstream-related protein P-ERK, downstream-related protein NLRP3 and Caspase1 after inflammatory injury of mouse articular chondrocytes. Results showed that the expression level of TXNIP in chondrocytes induced by different concentrations of il-1β was proportional to the concentration. After silencing TXNIP by shRNA, cell proliferation increased, chondrocyte apoptosis was weakened, and chondrocyte aging was weakened. The differential expression of genes such as TNF, IL-6, MMP3, MMP13, ADAMTS-5 and type II collagen and the differential expression of protein levels were relatively decreased. In addition, the expression of the upstream-related protein P-ERK did not change much when TXNIP was silenced, and the expression levels of the downstream-related proteins NLRP3 and Caspase1 were slightly reduced. In conclusion, silencing TXNIP can inhibit il-1β-induced chondrocyte apoptosis and aging, and has a positive effect on cell proliferation. However, this study has not clarified the molecular mechanism involved in TXNIP and the process of its signaling expression pathway.