Therapeutic Target For Osteoarthritis Research Articles

Investigation of GPM6B as a novel therapeutic target in Osteoarthritis.

Osteoarthritis (OA) is the most common motor system disease in older people, characterized by a high incidence and significant social and economic burden. Women have a higher risk of OA, more severe clinical symptoms, and a higher rate of disabilities than men. However, the pathogenesis of OA remains unclear. Therefore, we screened for differentially expressed genes (DEGs) in OA patients of different sex and searched for new targets that may be involved in regulating the development of OA. The study compared the expression of DEGs in synovial fluid exosomes between male and female patients with OA through RNA sequencing combined with bioinformatics analysis using public data. To evaluate the screened DEGs, synovial tissue and fluid samples were obtained from patients with OA who underwent joint replacement surgery. SiRNA-mediated knockdown in vitro experiments were performed to investigate the role of glycoprotein membrane 6B (GPM6B). Meanwhile, GPM6B gene knockout mice were used to assess the in vivo pathological roles of GPM6B in OA. The results revealed that GPM6B is a potential target associated with OA. Immunofluorescence staining demonstrated that GPM6B was expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes in patients with OA. In vitro experiments confirmed that GPM6B knockdown can reduce the expression of inflammatory factors in primary FLS from patients with OA. Under inflammatory conditions, GPM6B knockdown can reduce the expression of matrix metalloproteinases as well as proliferation of FLS. In addition, using a destabilization of the medial meniscus-induced OA model, we revealed that GPM6B is associated with OA progression in mice. Thus, we provided evidence that GPM6B act as a new target associated with OA.

From metabolomics to therapeutics: identifying causal metabolites and potential drugs for the treatment of osteoarthritis.

Osteoarthritis (OA) is a common age-related disease that causes pain and impaired mobility. Various blood metabolites are reportedly associated with bone health; however, their impact on OA remains unclear. Therefore, we conducted a metabolome-wide Mendelian randomization (MR) study to identify causal metabolites and therapeutic targets in OA. Genetic associations of metabolites were derived from the largest genome-wide association study (GWAS) of the blood metabolome, which provided summary-level data on 1091 blood metabolites. Genetic associations with OA were obtained from four large-scale GWAS: McDonald's study (140,025 cases, 344,349 controls), Zengini's study (12,658 cases, 50,898 controls), Dönertaş's study (39,515 cases, 445,083 controls), and Tachmazidou's study (39,427 cases, 378,169 controls). MR and colocalization analyses were performed to validate the causal roles of the candidate metabolites. Further analyses were conducted using expression quantitative trait locus-based MR, single-cell sequencing data, protein-protein interaction networks, and druggability assessments. These analyses aimed to identify the differentially expressed genes and prioritize them as potential therapeutic targets. The genetically predicted levels of 10 metabolites were associated with OA. Elevated levels of five metabolites and reduced levels of another five metabolites were associated with an increased OA risk. Among these, five metabolites were prioritized based on the most compelling evidence. Seven genes were identified as potentially involved and could serve as novel therapeutic targets for OA. Several blood metabolites were associated with OA, providing new insights into the etiology of OA and highlighting promising therapeutic targets.

Osteoarthritis year in review 2024: genetics, genomics, and epigenetics

ObjectiveThe purpose of this narrative review is to highlight the advances made in the past 12 months in the field of osteoarthritis genetics, genomics and epigenetics. MethodsThe Medline and Embase databases were systematically searched for original publications using terminology, and combinations of terminology, relating to: “osteoarthritis”, “genetics”, “genomics”, and “epigenetics”. Only original research articles published in the English language between the OARSI congresses of April 2032 and April 2024 were considered. ResultsThis narrative review focuses only on studies using genome-wide omics techniques in human material. There was a rise in functional genomics studies across different osteoarthritis-relevant tissues, which have robustly identified an additional 26 genes involved in osteoarthritis pathology. Two of such previously identified genes (MGP, ALDH1A2) are currently the target of ongoing clinical trials for osteoarthritis. This past year also saw the use of single-cell transcriptomics and two relatively new omics: epitranscriptomics and mitochondrial genomics. ConclusionThis past year of genomics research has led to multiple exciting findings involving genes and mechanisms linked to osteoarthritis. Moreover, the comprehensive genome-wide omics datasets generated for diverse osteoarthritis tissues will prove invaluable for future research aimed at elucidating more causal biological mechanisms and possible therapeutic targets for osteoarthritis.

Inflammation as a therapeutic target for osteoarthritis: A literature review of clinical trials.

The burden of osteoarthritis (OA) is rapidly increasing with population aging, but there are still no approved disease-modifying drugs available. Accumulating evidence has shown that OA is a heterogeneous disease with multiple phenotypes, and it is unlikely to respond to one-size-fits-all treatments. Inflammation is recognized as an important phenotype of OA and is associated with worse pain and joint deterioration. Therefore, it is believed that anti-inflammatory treatments may be more effective for OA with an inflammatory phenotype. In this review, we summarized clinical trials that evaluated anti-inflammatory treatments for OA and discussed whether these treatments are more effective in inflammatory OA phenotypes compared to general OA patients.

Proteome-Wide Mendelian Randomization and Colocalization Analysis Identify Therapeutic Targets for Knee and Hip Osteoarthritis.

Osteoarthritis (OA) is a common degenerative disease. Although some biomarkers and drug targets of OA have been discovered and employed, limitations and challenges still exist in the targeted therapy of OA. Mendelian randomization (MR) analysis has been regarded as a reliable analytic method to identify effective therapeutic targets. Thus, we aimed to identify novel therapeutic targets for OA and investigate their potential side effects based on MR analysis. In this study, two-sample MR, colocalization analysis, summary-data-based Mendelian randomization (SMR) and Mendelian randomization phenome-wide association study (MR-PheWAS) were conducted. We firstly analyzed data from 4907 plasma proteins to identify potential therapeutic targets associated with OA. In addition, blood expression quantitative trait loci (eQTLs) data sources were used to perform additional validation. A protein-protein interaction (PPI) network was also constructed to delve into the interactions among identified proteins. Then, MR-PheWASs were utilized to assess the potential side effects of core therapeutic targets. After MR analysis and FDR correction, we identified twelve proteins as potential therapeutic targets for knee OA or hip OA. Colocalization analysis and additional validation supported our findings, and PPI networks revealed the interactions among identified proteins. Finally, we identified MAPK3 (OR = 0.855, 95% CI: 0.791-0.923, p = 6.88 × 10-5) and GZMK (OR = 1.278, 95% CI: 1.131-1.444, p = 8.58 × 10-5) as the core therapeutic targets for knee OA, and ITIH1 (OR = 0.847, 95% CI: 0.784-0.915, p = 2.44 × 10-5) for hip OA. A further MR phenome-wide association study revealed the potential side effects of treatments targeting MAPK3, GZMK, and ITIH1. This comprehensive study indicates twelve plasma proteins with potential roles in knee and hip OA as therapeutic targets. This advancement holds promise for the progression of OA drug development, and paves the way for more efficacious treatments of OA.

Identification of therapeutic targets in osteoarthritis by combining heterogeneous transcriptional datasets, drug-induced expression profiles, and known drug-target interactions

BackgroundOsteoarthritis (OA) is a multifactorial, hypertrophic, and degenerative condition involving the whole joint and affecting a high percentage of middle-aged people. It is due to a combination of factors, although the pivotal mechanisms underlying the disease are still obscure. Moreover, current treatments are still poorly effective, and patients experience a painful and degenerative disease course.MethodsWe used an integrative approach that led us to extract a consensus signature from a meta-analysis of three different OA cohorts. We performed a network-based drug prioritization to detect the most relevant drugs targeting these genes and validated in vitro the most promising candidates. We also proposed a risk score based on a minimal set of genes to predict the OA clinical stage from RNA-Seq data.ResultsWe derived a consensus signature of 44 genes that we validated on an independent dataset. Using network analysis, we identified Resveratrol, Tenoxicam, Benzbromarone, Pirinixic Acid, and Mesalazine as putative drugs of interest for therapeutics in OA for anti-inflammatory properties. We also derived a list of seven gene-targets validated with functional RT-qPCR assays, confirming the in silico predictions. Finally, we identified a predictive subset of genes composed of DNER, TNFSF11, THBS3, LOXL3, TSPAN2, DYSF, ASPN and HTRA1 to compute the patient’s risk score. We validated this risk score on an independent dataset with a high AUC (0.875) and compared it with the same approach computed using the entire consensus signature (AUC 0.922).ConclusionsThe consensus signature highlights crucial mechanisms for disease progression. Moreover, these genes were associated with several candidate drugs that could represent potential innovative therapeutics. Furthermore, the patient’s risk scores can be used in clinical settings.

Intraarticular monomethyl fumarate as a perspective therapy for osteoarthritis by macrophage polarization.

Osteoarthritis (OA) is a chronic disease that may lead to joint structure degeneration, cartilage destruction, osteophyte formation, subchondral bone disruption, and pain. In this scenario, a higher proportion of the proinflammatory macrophage type 1 (M1) than the anti-inflammatory macrophage type 2 (M2) could be highlighted as a hallmark of OA progression. The balance between these two macrophage types emerges as a new therapeutic target in OA. This study aimed to evaluate the analgesia and macrophage profile in the treatment of experimental osteoarthritis (EOA) with systemic dimethyl fumarate (DMF) or local intra-articular monomethyl fumarate (MMF). DMF via gavage or MMF via intra-articular in the right knee of EOA rats showed improvements in gait parameters and the nociceptive recovery of the mechanical threshold assessment by adapted electronic von Frey treatment on the twenty-first day (long-lasting phase). DMF treatment decreased proinflammatory TNF-α while increasing anti-inflammatory IL-10 cytokines from the macerated capsule on the fifth day (inflammatory phase). MMF treatment showed joint capsule mRNA extraction downregulating iNOS and TNF-α gene expression while upregulating IL-10 and MCP-1. However, CD206 was not significant but higher than untreated EOA rats' joints on the seventh day (inflammatory phase). Our studies with EOA model induced by MIA suggest a new perspective for human treatment committed with OA based on macrophage polarization as a therapeutic target, switching the proinflammatory profile M1 to the anti-inflammatory profile M2 with DMF systematic or by MMF locally treatment according to the OA severity.

MiR-29a-3p mediates phosphatase and tensin homolog and inhibits osteoarthritis progression.

Despite substantial progress in clinical trials of osteoarthritis (OA) gene therapy, the prevalence of OA is still on the rise. MiRNAs have a potential biomarker and therapeutic target for OA. OA cartilage and chondrosarcoma cells were studied to determine the role of miR-29a-3p and PTEN. OA cartilage and human chondrosarcoma cells (SW1353) were obtained. miR-29a-3p and PTEN signature expression was determined by RT-qPCR. The binding relationship between miR-29a-3p and PTEN was investigated by dual-luciferase reporter gene and western blot assay. TUNEL, immunohistochemistry, CCK-8, and flow cytometry were utilized to determine the proliferation and apoptosis of SW1353 cells. This study indicated downregulation of miR-29a-3p expression and upregulation of PTEN expression in human OA primary chondrocytes or OA tissue samples, compared with the normal cartilage cells or tissues. PTEN expression was negatively correlated with miR-29a-3p expression, and miR-29a-3p targeted PTEN mechanistically. miR-29a-3p reduced SW1353 cell activity and proliferation and promoted cell apoptosis. However, the aforementioned effects could be reversed by downregulating PTEN. miR-29a-3p can stimulate chondrocyte proliferation and inhibit apoptosis by inhibiting PTEN expression.

Ion Channels As Emerging Metabolic Regulators and Therapeutic Targets in Osteoarthritis: Nav1.7 As a Recent Exemplar

Ion Channels As Emerging Metabolic Regulators and Therapeutic Targets in Osteoarthritis: Nav1.7 As a Recent Exemplar

Exploring m6A-linked aging genes in osteoarthritis and broad cancer spectrum: Prospects for diagnostic and therapeutic advancements.

Osteoarthritis (OA) is a prevalent degenerative joint disease that significantly impacts individuals and healthcare systems worldwide. However, the exploration of N6-methyladenosine (m6A)-related aging genes in OA pathogenesis remains largely underexplored. This study aimed to elucidate the role of m6A-related aging genes in OA and to develop a robust diagnostic model based on their expression profiles. Leveraging publicly available gene expression datasets, we conducted consensus clustering to categorize OA into distinct subtypes, guided by the expression patterns of m6A-related aging genes. Utilizing XGBoost, a cutting-edge machine learning approach, we identified key diagnostic genes and constructed a predictive model. Our investigation extended to the immune functions of these genes, shedding light on potential therapeutic targets and underlying regulatory mechanisms. Our analysis unveiled specific OA subtypes, each marked by unique expression profiles of m6A-related aging genes. We pinpointed a set of pivotal diagnostic genes, offering potential therapeutic avenues. The developed diagnostic model exhibited exceptional capability in distinguishing OA patients from healthy controls. To corroborate our computational findings, we performed quantitative real-time polymerase chain reaction analyses on two cell lines: HC-OA (representing adult osteoarthritis cells) and C-28/I2 (representative of normal human chondrocytes). The gene expression patterns observed were consistent with our bioinformatics predictions, further validating our initial results. In conclusion, this study underscores the significance of m6A-related aging genes as promising biomarkers for diagnosis and prognosis, as well as potential therapeutic targets in OA. Although these findings are encouraging, further validation and functional analyses are crucial for their clinical application.

Hsa_circular RNA_0045474 Facilitates Osteoarthritis Via Modulating microRNA-485-3p and Augmenting Transcription Factor 4.

Circular RNA (circRNA) influences on the pathological process of osteoarthritis (OA) and may be a potential marker for disease diagnosis. The study was to scrutinize the association of circ_0045474 with OA. Clinical samples of OA patients were collected, and 12 circRNAs derived from KPNA2 gene were examined. CHON-001 cells were stimulated with IL-1β to construct an OA chondrocyte model. miR-485-3p, transcription factor 4 (TCF4) and circ_0045474, type II procollagen (COL2A1), and human collagenase-3 (MMP13) were tested. Furthermore, cell activities were analyzed. The relationship between miR-485-3p, TCF4, and circ_0045474 was determined. The role of circ_0045474 in vivo was further confirmed by constructing an OA mouse model by anterior cruciate ligament transection. circ_0045474 expression was elevated in OA patients. Suppressing circ_0045474 restrained IL-1β-stimulated extracellular matrix degradation, inflammatory cytokine secretion, and chondrocyte apoptosis. Circ_0045474 competitively combined with miR-485-3p, while TCF4 was the target of miR-485-3p. Circ_0045474 modulated IL-1β-stimulated extracellular matrix degradation, inflammatory cytokine secretion, and chondrocyte apoptosis via miR-485-3p/TCF4 axis. Suppressing circ 0045474 was effective to alleviate OA in mice. Silenced circ_0045474 suppresses OA progression in vitro and vivo via miR-485-3p/TCF4 axis. In short, circ_0045474 can be considered a novel therapeutic target for OA.

Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.

Bifunctional TRPV1 Targeted Magnetothermal Switch to Attenuate Osteoarthritis Progression

Transient receptor potential vanilloid family member 1 (TRPV1) has been revealed as a therapeutic target of osteoarthritis (OA), the most common deteriorating whole joint disease, by impeding macrophagic inflammation and chondrocytes ferroptosis. However, the clinical application for capsaicin as the TRPV1 agonist is largely limited by its chronic toxicity. To address this issue, we developed a bifunctional controllable magnetothermal switch targeting TRPV1 for the alleviation of OA progression by coupling of magnetic nanoparticles (MNPs) to TRPV1 monoclonal antibodies (MNPs-TRPV1). Under the alternating magnetic field (AMF) stimulation, MNPs-TRPV1 locally dissipated heat, which was sufficient to trigger the opening and activation of TRPV1, and effectively impeded macrophagic inflammation and chondrocyte ferroptosis. This magnetothermal modulation of TRPV1 simultaneously attenuated synovitis and cartilage degeneration in mice incurred by destabilization of medial meniscus surgery, indicating the delayed OA progression. Furthermore, MNPs-TRPV1 with AMF exposure remarkably reduced knee pain sensitivity, alleviated the crippled gait, and improved spontaneous ambulatory activity performance in the mice OA model. Overall, this work provides a potential pathogenesis-based precise OA therapy with temporally and spatially magnetothermal modulation of TRPV1 in a controllable manner.

The IRF1/GBP5 axis promotes osteoarthritis progression by activating chondrocyte pyroptosis

BackgroundOsteoarthritis (OA) is a chronic degenerative joint disease that primarily affects middle-aged and elderly individuals. The decline in chondrocyte function plays a crucial role in the development of OA. Inflammasome-mediated chondrocyte pyroptosis is implicated in matrix degradation and cartilage degeneration in OA patients. Guanylate binding protein 5 (GBP5), a member of the GTPase family induced by Interferon-γ (IFN-γ), significantly influences cellular inflammatory responses, including intracellular inflammasome activation and cytokine release. However, the role of GBP5 in chondrocyte pyroptosis and OA progression remains unclear. MethodsIn this study, we used tumor necrosis factor-α (TNF-α) to induce inflammation and created an OA mouse model with surgically-induced destabilization of the medial meniscus (DMM). We isolated and cultured primary chondrocytes from the knee joints of suckling C57 mice. TNF-α-stimulated primary chondrocytes served as an in vitro model for OA and underwent RNA sequencing. Chondrocytes were transfected with GBP5-overexpression plasmids and small interfering RNA and were subsequently treated with TNF-α. We assessed the expression of cartilage matrix components (COL2A1 and aggrecan), catabolic factors (MMP9 and MMP13), and NLRP3 inflammasome pathway genes (NLRP3, Caspase1, GSDMD, Pro-IL-1β, and Pro-Caspase1) using RT-qPCR and Western blotting. We analyzed the expression of GBP5, NLRP3, and Caspase1 in the cartilage of DMM-induced post-traumatic OA mice and human OA patients. Immunohistochemistry (IHC) was used to detect the expression of GBP5, NLRP3 and GSDMD in cartilage specimens from OA patients and mouse DMM models. Chondrocyte pyroptosis was assessed using flow cytometry, and the levels of interleukin-1β (IL-1β) and interleukin-18 (IL-18) were measured with ELISA. We conducted double luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays to confirm the relationship between IRF1 and GBP5. ResultsGBP5 expression increased in TNF-α-induced chondrocytes, as revealed by RNA sequencing. GBP5 inhibited COL2A1 and aggrecan expression while promoting the expression of MMP9, MMP13, NLRP3, Caspase1, GSDMD, Pro-IL-1β, and Pro-Caspase1. GBP5 expression also increased in the cartilage of DMM-induced post-traumatic OA mice and human OA patients. Knockout of GBP5 reduced chondrocyte injury in OA mice. GBP5 promoted chondrocyte pyroptosis and the production of IL-1β and IL-18. Additionally, we found that IRF1 bound to the promoter region of GBP5, enhancing its expression. After co-transfected with ad-IRF1 and siGBP5, the expression of pyroptosis-related genes was significantly decreased compared with ad-IRF1 group. ConclusionsThe IRF1/GBP5 axis enhances extracellular matrix (ECM) degradation and promotes pyroptosis during OA development, through the NLRP3 inflammasome signaling pathway. The translational potential of this articleThis study underscores the significance of the IRF1/GBP5 axis in NLRP3 inflammasome-mediated chondrocyte pyroptosis and osteoarthritic chondrocyte injury. Modulating IRF1 and GBP5 expression could serve as a novel therapeutic target for OA.

CircIRAK3 exerts negative feedback regulation on inflammation by binding to HNRNP U and destabilizing proinflammatory cytokine mRNA in osteoarthritis and chondrogenesis

Osteoarthritis (OA) is the most prevalent age-related and degenerative joint disease with limited treatment options. Previous studies have identified the therapeutic effects of mesenchymal stem cells (MSCs) therapy. Nevertheless, chronic inflammation impedes MSCs therapeutic effect. There have been reports suggesting that circular RNAs (circRNAs) are involved in OA and chondrogenesis. The combination of MSCs and circRNAs in therapies appears to be a promising option. In this study, we identified circIRAK3 as a significant regulator in cartilage degeneration and chondrogenesis through high-throughput sequencing analyses. We observed increased circIRAK3 in OA cartilage and during MSCs chondrogenesis. Knockdown of circIRAK3 resulted in excessive apoptosis, inhibited proliferation, and degradation of chondrocytes, along with the inhibition of MSCs chondrogenesis. Mechanistically, circIRAK3 bound to HNRNP U and competitively prevented its binding to IL-1β, TNFα, and IL6 mRNA, thereby promoting mRNA degradation. Notably, circIRAK3 expression in plasma increased with higher OARSI scores. Intra-articular injection of adeno-associated virus-circIRAK3 delayed cartilage degeneration and reduced inflammation in DMM mouse model. Our study highlights a compensatory regulation network of circIRAK3 in chondrocytes in response to inflammation. CircIRAK3 has the potential to serve as a new therapeutic target for OA. Furthermore, therapies targeting circIRAK3 combined with MSCs hold promise.

Comprehensive characterization of pathogenic synovial fluid extracellular vesicles from knee osteoarthritis

Synovial fluid (SF) extracellular vesicles (EVs) play a pathogenic role in osteoarthritis (OA). However, the surface markers, cell and tissue origins, and effectors of these EVs are largely unknown. We found that SF EVs contained 692 peptides that were positively associated with knee radiographic OA severity; 57.4% of these pathogenic peptides were from 46 proteins of the immune system, predominantly the innate immune system. CSPG4, BGN, NRP1, and CD109 are the major surface markers of pathogenic SF EVs. Genes encoding surface marker CSPG4 and CD109 were highly expressed by chondrocytes from damaged cartilage, while VISG4, MARCO, CD163 and NRP1 were enriched in the synovial immune cells. The frequency of CSPG4+ and VSIG4+ EV subpopulations in OA SF was high. We conclude that pathogenic SF EVs carry knee OA severity-associated proteins and specific surface markers, which could be developed as a new source of diagnostic biomarkers or therapeutic targets in OA.

PSD95 as a New Potential Therapeutic Target of Osteoarthritis: A Study of the Identification of Hub Genes through Self-Contrast Model.

Osteoarthritis (OA) is a worldwide joint disease. However, the precise mechanism causing OA remains unclear. Our primary aim was to identify vital biomarkers associated with the mechano-inflammatory aspect of OA, providing potential diagnostic and therapeutic targets for OA. Thirty OA patients who underwent total knee arthroplasty were recruited, and cartilage samples were obtained from both the lateral tibial plateau (LTP) and medial tibial plateau (MTP). GO and KEGG enrichment analyses were performed, and the protein-protein interaction (PPI) assessment was conducted for hub genes. The effect of PSD95 inhibition on cartilage degeneration was also conducted and analyzed. A total of 1247 upregulated and 244 downregulated DEGs were identified. Significant differences were observed between MTP and LTP in mechanical stress-related genes and activated sensory neurons based on a self-contrast model of human knee OA. Cluster analysis identified DLG4 as the hub gene. Cyclic loading stress increased PSD95 (encoded by DLG4) expression in LTP cartilage, and PSD95 inhibitors could alleviate OA progression. This study suggests that inhibiting PSD95 could be a potential therapeutic strategy for preventing articular cartilage degradation.

Identification and analysis of RNA-5-methylcytosine-related key genes in osteoarthritis

Background5-methylcytosine (m5C) modification is widely associated with many biological and pathological processes. However, knowledge of m5C modification in osteoarthritis (OA) remains lacking. Thus, our study aimed to identify common m5C features in OA.ResultsIn the present study, we identified 1395 differentially methylated genes (DMGs) and 1673 differentially expressed genes (DEGs) using methylated RNA immunoprecipitation next-generation sequencing (MeRIP-seq) and RNA-sequencing. A co-expression analysis of DMGs and DEGs showed that the expression of 133 genes was significantly affected by m5C methylation. A protein–protein interaction network of the 133 genes was constructed using the STRING database, and the cytoHubba plug-in of Cytoscape was used to hub genes were screen out 11 hub genes, including MMP14, VTN, COL15A1, COL6A2, SPARC, COL5A1, COL6A3, COL6A1, COL8A2, ADAMTS2 and COL7A1. The Pathway enrichment analysis by the ClueGO and CluePedia plugins in Cytoscape showed that the hub genes were significantly enriched in collagen degradation and extracellular matrix degradation.ConclusionsOur study indicated that m5C modification might play an important role in OA pathogenesis, and the present study provides worthwhile insight into identifying m5C-related therapeutic targets in OA.

Suramin analogues protect cartilage against osteoarthritic breakdown by increasing levels of tissue inhibitor of metalloproteinases 3 (TIMP-3) in the tissue

Osteoarthritis is a chronic degenerative joint disease affecting millions of people worldwide, with no disease-modifying drugs currently available to treat the disease. Tissue inhibitor of metalloproteinases 3 (TIMP-3) is a potential therapeutic target in osteoarthritis because of its ability to inhibit the catabolic metalloproteinases that drive joint damage by degrading the cartilage extracellular matrix. We previously found that suramin inhibits cartilage degradation through its ability to block endocytosis and intracellular degradation of TIMP-3 by low-density lipoprotein receptor-related protein 1 (LRP1), and analysis of commercially available suramin analogues indicated the importance of the 1,3,5-trisulfonic acid substitutions on the terminal naphthalene rings for this activity. Here we describe synthesis and structure–activity relationship analysis of additional suramin analogues using ex vivo models of TIMP-3 trafficking and cartilage degradation. This showed that 1,3,6-trisulfonic acid substitution of the terminal naphthalene rings was also effective, and that the protective activity of suramin analogues depended on the presence of a rigid phenyl-containing central region, with para/para substitution of these phenyl rings being most favourable. Truncated analogues lost protective activity. The physicochemical characteristics of suramin and its analogues indicate that approaches such as intra-articular injection would be required to develop them for therapeutic use.

Drug Delivery Strategies and Nanozyme Technologies to Overcome Limitations for Targeting Oxidative Stress in Osteoarthritis.

Oxidative stress is an important, but elusive, therapeutic target for osteoarthritis (OA). Antioxidant strategies that target oxidative stress through the elimination of reactive oxygen species (ROS) have been widely evaluated for OA but are limited by the physiological characteristics of the joint. Current hallmarks in antioxidant treatment strategies include poor bioavailability, poor stability, and poor retention in the joint. For example, oral intake of exogenous antioxidants has limited access to the joint space, and intra-articular injections require frequent dosing to provide therapeutic effects. Advancements in ROS-scavenging nanomaterials, also known as nanozymes, leverage bioactive material properties to improve delivery and retention. Material properties of nanozymes can be tuned to overcome physiological barriers in the knee. However, the clinical application of these nanozymes is still limited, and studies to understand their utility in treating OA are still in their infancy. The objective of this review is to evaluate current antioxidant treatment strategies and the development of nanozymes as a potential alternative to conventional small molecules and enzymes.