Osteoarthritis Tissue Research Articles

ITGB5 as a Potential Diagnostic Biomarker for Osteoarthritis.

Osteoarthritis (OA) is a prevalent degenerative joint disease, especially occur in the elderly. This study aimed to uncover a novel biomarker for early diagnosis and treatment of OA. WGCNA, differential expression analysis and PPI network were used for screening hub genes-related to OA, utilizing the GSE55235 and GSE57218 datasets from GEO database. Based on the data in the GEO datasets, compared to normal tissues, ITGB5 was obviously elevated in OA cartilage and synovial samples. Additionally, ROC curve results validated the diagnostic value of ITGB5 in OA. Mechanistically, transcription factors KLF4 and KLF11 could modulate ITGB5 gene transcription via binding to its promoter region, thereby affecting ITGB5 gene expression in OA tissues. GSEA results showed that ITGB5 gene was closely related to p53, wnt, TNF and T cell receptor signaling pathways, suggesting that ITGB5 may play potential roles in affecting cell apoptosis and inflammation in OA. Moreover, ITGB5 levels in OA samples was positively correlated to T helper type 1 cells, natural killer T cells, macrophages, memory CD8 T cells, activated dendritic cells. In this study, we found that ITGB5 was obviously elevated in OA samples. Moreover, ITGB5 may function as a diagnostic biomarker in OA.

Circulating miR-126-3p is a mechanistic biomarker for knee osteoarthritis

Osteoarthritis is a major contributor to pain and disability worldwide, yet there are currently no validated soluble biomarkers or disease-modifying treatments. Given that microRNAs are promising mechanistic biomarkers that can be therapeutically targeted, in this study, we aimed to identify and prioritize reproducible circulating microRNAs associated with radiographic knee osteoarthritis. Across four independent cohorts, we find circulating miR-126-3p is elevated in knee osteoarthritis versus controls. Across six primary human knee osteoarthritis tissues, miR-126-3p is highest in subchondral bone, fat pad and synovium, and lowest in cartilage. Following both intravenous and intra-articular miR-126-3p mimic treatment in a surgical mouse model of knee osteoarthritis, we show reduced disease severity in males. In human knee osteoarthritis biospecimens, miR-126-3p mimic treatment reduces genes and markers associated with angiogenesis, as well as genes linked to osteogenesis, adipogenesis, and synovitis—processes secondary to angiogenesis. Our findings indicate that miR-126-3p is elevated in knee osteoarthritis and mitigates disease severity, supporting its potential as a biomarker and therapeutic target.

Matrikine stimulation of equine synovial fibroblasts and chondrocytes results in an in vitro osteoarthritis phenotype.

Osteoarthritis (OA) is a debilitating disease that impacts millions of individuals and has limited therapeutic options. A significant hindrance to therapeutic discovery is the lack of in vitro OA models that translate reliably to in vivo preclinical animal models. An alternative to traditional inflammatory cytokine models is the matrikine stimulation model, in which fragments of matrix proteins naturally found in OA tissues and synovial fluid, are used to stimulate cells of the joint. The objective of this study was to determine if matrikine stimulation of equine synovial fibroblasts and chondrocytes with fibronectin fragments (FN7-10) would result in an OA phenotype. We hypothesized that FN7-10 stimulation of equine articular cells would result in an OA phenotype with gene and protein expression changes similar to those previously described for human chondrocytes stimulated with FN7-10. Synovial fibroblasts and chondrocytes isolated from four horses were stimulated in monolayer culture for 6 or 18 h with 1 µM purified recombinant 42 kD FN7-10 in serum-free media. At the conclusion of stimulation, RNA was collected for targeted gene expression analysis and media for targeted protein production analysis. Consistent with our hypothesis, FN7-10 stimulation resulted in significant alterations to many important genes that are involved in OA pathogenesis including increased expression of IL-1β, IL-4, IL-6, CCL2/MCP-1, CCL5/RANTES, CXCL6/GCP-2, MMP-1, MMP-3, and MMP13. The results of this study suggest that the equine matrikine stimulation model of OA may prove useful for in vitro experiments leading up to preclinical trials.

WTAP improves chondrocyte loss and dysfunctions to ameliorate osteoarthritis through mediating the mA methylation and mRNA stability of IL-33.

WTAP improves chondrocyte loss and dysfunctions to ameliorate osteoarthritis through mediating the mA methylation and mRNA stability of IL-33.

Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases.

Bone metabolism in bone tissue is constantly maintained in a state of dynamic equilibrium. The mass of bone and joint tissues is determined by both bone formation and bone resorption. It is hypothesized that disrupted metabolic balance leads to osteoporosis, osteoarthritis, rheumatoid arthritis, and bone tumors. Such disruptions often manifest as either a reduction or abnormality in bone mass and are frequently accompanied by pathological changes such as inflammation, fractures, and pain. α-Ketoglutarate (α-KG) serves as a pivotal intermediate in various metabolic pathways in mammals, significantly contributing to cellular energy metabolism, amino acid metabolism, and other physiological processes. α-KG may be a therapeutic target for a variety of bone-related diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, because of its role in maintaining the metabolic balance of bone. After the application of α-KG, bone loss and inflammation in bone tissue are alleviated. This review focuses on the regulatory effects of α-KG on various cells in bone and joint tissues. Owing to the regulatory effect of α-KG on the balance of bone metabolism, the application of α-KG in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, bone tumors, and other bone tissue diseases has been clarified.

An Innovative Anoikis Signature With Inflammatory Infiltrates in Osteoarthritis.

To explore the relationship between an innovative anoikis-related gene signature and inflammatory infiltrates in patients with osteoarthritis. Gene expression profiles (GSM1248759 and GSE200843) were curated from the Gene Expression Omnibus database, followed by the construction of a protein-protein interaction network. Functional and genomic enrichment analyses were conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The CIBERSORT method was employed to investigate immune cell infiltration differences between osteoarthritic and control tissues. Additionally, the ConsensusClusterPlus package in R software was utilized to identify distinct anoikis patterns (Cluster C1 and Cluster C2) and conduct molecular biological investigations. Analysis revealed two distinct anoikis patterns (Cluster C1 and Cluster C2), with Cluster C2 patients exhibiting varying immune cell levels compared to Cluster C1 patients. Molecular investigations identified 84 DEGs enriched in specific pathways such as adipocytokine signaling, cytokine-cytokine receptor interaction, ECM-receptor interaction, and the PPAR signaling pathway. qPCR experiments confirmed the elevated expression levels of specific genes, including SOD2, MAPK14, CEACM3, LAMB3, COL13A1, TLR3, NOTCH3, and KLF12, in the IL-1β-induced group compared with the osteoarthritis group. This study highlights the role of anoikis-related genes and immune infiltration differences in osteoarthritis, enhancing our understanding of its development.

Tissue and Extracellular Matrix Remodeling of the Subchondral Bone during Osteoarthritis of Knee Joints as revealed by Spatial Mass Spectrometry Imaging.

Osteoarthritis (OA) is a degenerative condition of the skeletal extracellular matrix (ECM) marked by the loss of articular cartilage and changes to subchondral bone homeostasis. Treatments for OA beyond full joint replacement are lacking primarily due to gaps in molecular knowledge of the biological drivers of disease. Mass Spectrometry Imaging (MSI) enables molecular spatial mapping of the proteomic landscape of tissues. Histologic sections of human tibial plateaus from knees of human OA patients and cadaveric controls were treated with collagenase III to target ECM proteins prior to MS Imaging of bone and cartilage proteins using a timsTOF fleX mass spectrometer. Spatial MSI data of the knee were processed and automatically segmented identifying distinct areas of knee joint damage. ECM peptide markers were compared between i) the medial halves of OA patient joints and the medial side of non-OA (cadaveric) joints, and ii) between the same medial OA tissues and their corresponding, less OA impacted, lateral joint halves. Distinct peptide signatures distinguished OA medial tissues from the cadaveric medial and OA lateral tissues (AUROC >0.85). Overall, 31 peptide candidates from ECM proteins, including Collagen alpha-1(I), Collagen alpha-1(III), and surprisingly, Collagen alpha-1(VI) and Collagen alpha-3(VI), exhibited significantly elevated abundance in diseased tissues. Highly specific hydroxyproline-containing collagen peptides, mainly from collagen type I, dominated OA subchondral bone directly under regions of lost cartilage. The identification of specific protein markers for subchondral bone remodeling in OA advances our molecular understanding of disease progression in OA and provides potential new biomarkers for OA detection and disease grading.

Identification of WDR74 and TNFRSF12A as biomarkers for early osteoarthritis using machine learning and immunohistochemistry.

Osteoarthritis (OA) is a chronic joint condition that causes pain, limited mobility, and reduced quality of life, posing a threat to healthy aging. Early detection is crucial for improving prognosis. Recent research has focused on the role of ubiquitination-related genes (URGs) in early OA prediction. This study aims to integrate URG expression data with machine learning (ML) to identify biomarkers that improve diagnosis and prognosis in the early stages of OA. OA single-cell RNA sequencing datasets were collected from the GEO database. Single-cell analysis was performed to investigate the composition and relationships of chondrocytes in OA. The potential intercellular communication mechanisms were explored using the CellChat R package. URGs were retrieved from GeneCards, and ubiquitination scores were calculated using the AUCell package. Gene module analysis based on co-expression network analysis was conducted to identify core genes. Additionally, ML analysis was performed to identify core URGs and construct a diagnostic model. We employed XGBoost, a gradient-boosting ML algorithm, to identify core URGs and construct a diagnostic model. The model's performance was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. In addition, we explored the relationship between core URGs and immune processes. The ChEA3 database was utilized to predict the transcription factors regulated by core ubiquitination-related genes. The expression of select URGs was validated using qRT-PCR and immunohistochemistry (IHC). We identified WDR74 and TNFRSF12A as pivotal ubiquitination-related genes associated with OA, exhibiting considerable differential expression. The diagnostic model constructed with URGs exhibited remarkable accuracy, with area under the curve (AUC) values consistently exceeding 0.9. The expression levels of WDR74 and TNFRSF12A were significantly higher in the IL-1β-induced group in an in vitro qPCR experiment. The IHC validation on human knee joint specimens confirmed the upregulation of WDR74 and TNFRSF12A in OA tissues, corroborating their potential as diagnostic biomarkers. WDR74 and TNFRSF12A as principal biomarkers highlighted their attractiveness as therapeutic targets. The identification of core biomarkers might facilitate early intervention options, potentially modifying the illness trajectory and enhancing patient outcomes.

The Impact of the Yeoh Model's Variability in Contact on Knee Joint Mechanics.

The aim of this study was to assess the impact of the variability of the Yeoh model when modeling the contact of bones through cartilage in the knee in compression and flexion-extension within a hybrid knee model. Firstly, a Sobol sequence of 64 samples and four variables representing the Yeoh parameters of the cartilage of the femur and tibia was generated. Based on these samples, 2 × 64 finite element contact models of the geometry of the sphere plane were generated and solved for healthy tissue affected by osteoarthritis. The resulting indentation curves were incorporated into a multibody knee joint model. The obtained results suggested that cartilage variability severely affected the knee in compression by up to 32%. However, the same variability also affected the flexion-extension motion, although to a lesser extent, with a relative change to the range of angular displacements of almost 7%. Osteoarthritic tissue was consistently more affected by this variability, suggesting that when modeling degenerated tissue, complex joint models are necessary.

LncRNA-HHCP5 Regulates KLF5 in ceRNA and m6A Pathways to Inhibit the Progression of Osteoarthritis.

Osteoarthritis (OA) is one of the most common bone disorders and has a serious impact on the quality of life of patients. LncRNA-HCP5 (HCP5) is downregulated in OA tissues. However, the latent function and regulatory mechanisms of HCP5 in OA are unclear. In the current study, IL-1β-induced C28/I2 cells were used to establish an invitro model of OA. The expression of HCP5 in OA cartilage tissue and in the invitro model of OA was detected by RT-qPCR. Cell viability and apoptosis were assessed by CCK-8 and Annexin V-PI double staining. Western blotting was employed to detect the protein expression of MMP-13 and aggrecan. The results showed that the findings suggested that HCP5 was downregulated in OA cartilage tissue and IL-1β-induced C28/I2 cells. HCP5 overexpression greatly enhanced IL-1β-induced proliferation of C28/I2 cells, as well as prevented cell apoptosis and degradation of extracellular matrix (ECM). Besides, we have shown that HCP5 is a ceRNA that regulates KLF5 by sponging miR-375. Furthermore, KLF5 is also regulated by m6A regulation induced by HCP5. Finally, overexpression of miR-375, the m6A modification inhibitor, as well as KLF5 inhibition reversed the impact of HCP5 on IL-1β-induced C28/I2 cells. In summary, the present study demonstrated that the HCP5/KLF5 axis inhibited the progression of osteoarthritis.

B Cell Activation, Differentiation, and Their Potential Molecular Mechanisms in Osteoarthritic Synovial Tissue.

The objective of this study was to characterize the activation and differentiation of B cells in the synovium of osteoarthritis (OA) and to explore the underlying molecular mechanisms. Peripheral blood and synovial samples from OA patients at different stages were collected, and flow cytometry was employed to analyze the activation and differentiation of B cells. Immunofluorescence staining of joint synovium from OA mice at different stages was conducted to assess mice joint synovium B cell activation and differentiation. Co-culture experiments of synovial fibroblasts with B cells were performed to investigate the influence of synovial cells on B cell activation and differentiation. Finally, transcriptome analysis was utilized to identify potential key molecules and pathways. In OA patients, the infiltration, activation, and differentiation of B cells in synovium and peripheral blood exhibited distinct characteristics. Specifically, the proportion of activated CD86+ B cells and the differentiation marker HLA-DR+ increased with disease severity, whereas the proportion of the differentiation marker IgM decreased. The proportion of CD38+ B cells also decreased with increasing severity, although this change lacked statistical significance. Immunofluorescence staining of CD19+ and CD86+ cells in mice indicated increased expression with greater OA severity. Co-culture experiments demonstrated that OA synovial fibroblasts promoted B cell activation and differentiation, as evidenced by higher expression levels of CD86+ and HLA-DR+ in the OA group compared to controls. Additionally, the proportion of naive B cells decreased as disease severity progressed. Synovial fibroblasts in OA have been shown to promote the differentiation and activation of B cells, indicating that B cells play a significant role in the pathogenesis of synovium inflammation in OA.

Comprehensive Analysis of Programmed Cell Death-Related Genes in Diagnosis and Synovitis During Osteoarthritis Development: Based on Bulk and Single-Cell RNA Sequencing Data.

Synovitis is one of the key pathological feature driving osteoarthritis (OA) development. Diverse programmed cell death (PCD) pathways are closely linked to the pathogenesis of OA, but few studies have explored the relationship between PCD-related genes and synovitis. The transcriptome expression profiles of OA synovial samples were obtained from the Gene Expression Omnibus (GEO) database. Using machine learning algorithms, Hub PCD-related differentially expressed genes (Hub PCD-DEGs) were identified. The expression of Hub PCD-DEGs was validated in human OA samples by qRT-PCR. A diagnostic model for OA was constructed based on the expression levels of Hub PCD-DEGs. Unsupervised consensus clustering analysis and weighted correlation network analysis (WGCNA) were employed to identify differential clustering patterns of PCD-related genes in OA patients. The molecular characteristics of Hub PCD-DEGs, their role in synovial immune inflammation, and their association with the immune microenvironment were investigated through functional enrichment analysis and ssGSEA immune infiltration analysis. Single-cell RNA sequencing analysis provided insights into the characteristics of distinct cell clusters in OA synovial tissues and their interactions with Hub PCD-DEGs. We identified five Hub PCD-DEGs: TNFAIP3, JUN, PPP1R15A, INHBB, and DDIT4. qRT-PCR analysis confirmed that all five genes were significantly downregulated in OA synovial tissue. The diagnostic model constructed based on these Hub PCD-DEGs demonstrated diagnostic efficiency in distinguishing OA tissues as well as progression of OA. Additionally, a correlation was observed between the expression levels of Hub PCD-DEGs, immune cell infiltration, and inflammatory cytokine levels. We identified two distinct PCD clusters, each exhibiting unique molecular and immunological characteristics. Single-cell RNA sequencing further revealed dynamic and complex cellular changes in OA synovial tissue, with differential expression of Hub PCD-DEGs across various immune cell types. Our study suggests that PCD-related genes may be involved in development of OA synovitis. The five screened Hub PCD-DEGs (TNFAIP3, JUN, PPP1R15A, INHBB and DDIT4) could be explored as candidate biomarkers or therapeutic targets for OA.

Circ-PDE1C/miR-766-3p/SGTB axis regulates the IL-1β-induced apoptosis, inflammation and oxidative stress in human chondrocytes

Abstract Background Osteoarthritis (OA) is a common degenerative joint disease. Circular RNA Phosphodiesterase 1 C (circ-PDE1C, hsa_circ_0134111) has participated in the IL-1β-induced chondrocyte damages. The objective of our study was to explore the molecular mechanism of circ-PDE1C. Methods Circ-PDE1C, microRNA-766-3p (miR-766-3p) or Small Glutamine Rich Tetratricopeptide Repeat Co-Chaperone Beta (SGTB) expression was determined using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Cell counting kit-8 (CCK-8) assay and flow cytometry were used to analyze proliferation and apoptosis, respectively. Western blotting assay was performed for protein detection. The inflammatory cytokines were measured by Enzyme-linked immunosorbent assay (ELISA). Oxidative stress was assessed by commercial kits. Target analysis was conducted by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Results Circ-PDE1C was abnormally overexpressed in OA tissues and IL-1β-exposed chondrocytes. Downregulation of circ-PDE1C alleviated the IL-1β-induced cell apoptosis, inflammation, extracellular matrix degradation and oxidative stress. Circ-PDE1C could interact with miR-766-3p to serve as miRNA sponge. The function of si-circ-PDE1C was attributed to the inhibition of miR-766-3p. Additionally, miR-766-3p directly targeted the 3’UTR of SGTB. The miR-766-3p upregulation impeded the IL-1β-triggered cell damages through reducing the level of SGTB. Moreover, SGTB expression was regulated by circ-PDE1C via binding to miR-766-3p in IL-1β-induced chondrocytes. Conclusion Altogether, circ-PDE1C enhanced the IL-1β-induced dysfunction in chondrocytes via upregulating SGTB by targeting miR-766-3p.

CRNDE alleviates IL-1β-induced chondrocyte damage by modulating miR-31/NF-κB pathway

BackgroundThe long non-coding RNA CRNDE (CRNDE) has been identified as a lncRNA associated with osteoarthritis (OA), playing a role the age-related degeneration of articular cartilage. However, the precise mechanism by which CRNDE affects the physiological functions of OA chondrocytes remains unclear.MethodsTo simulate the inflammatory conditions observed in OA, interleukin (IL)-1β-stimulated chondrocyte C-28/I2 cells were utilized. The expression levels of CRNDE and miR-31 were assessed using reverse transcription-polymerase chain reaction (RT-PCR). Chondrocyte viability and apoptosis were evaluated through CCK-8 assay and flow cytometry, respectively. The levels of IL-6, IL-1β and Tumor necrosis factor (TNF-α) were determined using enzyme-linked immunosorbent assay (ELISA). mRNA expression levels of MMP-13, Aggrecan and COL2A1 were detected by quantitative RT-PCR. Western blot analysis was performed to evaluate the protein levels of factors related to cartilage matrix degradation, including p-p65, p65 and p-IκBα of the NF-κB pathway.ResultsCRNDE expression was downregulated in both OA cartilage tissues and IL-1β-stimulated chondrocytes. Overexpression of CRNDE mitigated IL-1β-stimulated chondrocytes apoptosis, inflammatory responses, and cartilage matrix degradation. Compared with healthy controls, OA tissues exhibited reduced expression of miR-31, which was negatively correlated with the expression of CRNDE. Additionally, overexpression of miR-31 partially reversed the inhibitory effects of CRNDE on apoptosis, inflammation, cartilage matrix degradation, and the inactivation of Nuclear factor (NF)-κB pathway induced by IL-1β stimulation. Moreover, silencing of CRNDE exacerbated IL-1β-induced chondrocytes damage, which was aliviated by the NF-κB pathway inhibitor, Bay 11-7082.ConclusionCRNDE alleviated IL-1β-induced injuries in OA chondrocytes by suppressing the miR-31-mediated NF-κB signaling pathway.

Defining the extracellular matrix in non-cartilage soft-tissues in osteoarthritis: a systematic review.

Extracellular matrix (ECM) is a critical determinant of tissue mechanobiology, yet remains poorly characterized in joint tissues beyond cartilage in osteoarthritis (OA). This review aimed to define the composition and architecture of non-cartilage soft joint tissue structural ECM in human OA, and to compare the changes observed in humans with those seen in animal models of the disease. A systematic search strategy, devised using relevant matrix, tissue, and disease nomenclature, was run through the MEDLINE, Embase, and Scopus databases. Demographic, clinical, and biological data were extracted from eligible studies. Bias analysis was performed. A total of 161 studies were included, which covered capsule, ligaments, meniscus, skeletal muscle, synovium, and tendon in both humans and animals, and fat pad and intervertebral disc in humans only. These studies covered a wide variety of ECM features, including individual ECM components (i.e. collagens, proteoglycans, and glycoproteins), ECM architecture (i.e. collagen fibre organization and diameter), and viscoelastic properties (i.e. elastic and compressive modulus). Some ECM changes, notably calcification and the loss of collagen fibre organization, have been extensively studied across osteoarthritic tissues. However, most ECM features were only studied by one or a few papers in each tissue. When comparisons were possible, the results from animal experiments largely concurred with those from human studies, although some findings were contradictory. Changes in ECM composition and architecture occur throughout non-cartilage soft tissues in the osteoarthritic joint, but most of these remain poorly defined due to the low number of studies and lack of healthy comparator groups.

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

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

Substrate stiffness regulates the proliferation and inflammation of chondrocytes and macrophages through exosomes.

Substrate stiffness regulates the proliferation and inflammation of chondrocytes and macrophages through exosomes.

Investigating Angiogenesis-Related Biomarkers in Osteoarthritis Patients Through Transcriptomic Profiling.

Osteoarthritis (OA) is a common age-related joint disease characterized by joint destruction and impaired quality of life. Angiogenesis plays a vital role in OA progression. This study aimed to identify key angiogenesis-related genes (ARGs) in OA using transcriptomic and machine learning methods. The GSE55235 dataset (10 OA and 10healthy synovial tissue samples) was analyzed for differentially expressed genes (DEGs), integrated with weighted gene co-expression network analysis (WGCNA), and ARGs to identify differentially expressed ARGs (DE-ARGs). Candidate genes were identified through three machine learning algorithms and evaluated using ROC curve analysis. Gene set enrichment analysis (GSEA), immune cell infiltration analysis, and therapeutic agent prediction were performed. Synovial samples from 5 OA patients and 5 matched controls were collected for RT-qPCR validation of biomarkers. From 1552 DEGs, 11 DE-ARGs were identified, and six candidate genes were selected using machine learning. Four genes-COL3A1, OLR1, STC1, and KCNJ8-showed AUC >0.8 in both GSE55235 and GSE1919, indicating strong diagnostic value. GSEA linked biomarkers to the "lysosome" pathway, and eosinophils and Th2 cells were significantly associated with biomarkers. Potential therapeutic agents included bisphenol A, tetrachlorodibenzo-p-dioxin, and valproic acid. Clinical validation confirmed that COL3A1, OLR1, and STC1 expression levels were consistent with database findings. The study identified COL3A1, OLR1, STC1, and KCNJ8 as key angiogenesis-related biomarkers in osteoarthritis, which could serve as potential diagnostic tools and therapeutic targets. The research underscores the importance of angiogenesis in osteoarthritis progression and suggests that targeting angiogenesis-related pathways may offer new treatment strategies.

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

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

RIP1 inhibition reduces chondrocyte apoptosis through downregulating nuclear factor-kappa B signaling in a mouse osteoarthritis model.

Excessive chondrocyte death is a critical player in the process of osteoarthritis (OA). The present study was aimed to study the role of receptor-interacting serine/threonine kinase (RIP) 1-mediated signaling for programmed cell death in OA. In the present study, RIP1 protein expression was evaluated in mouse OA cartilage and cultured primary murine chondrocytes exposed to tumor necrosis factor-alpha (TNF-α). Protein expression involved in necroptosis and apoptosis and chondrocyte-derived extracellular matrix were examined. Inhibition of RIP1 was conducted using the RNAi technique and pharmacological inhibition. Western blot, immunohistochemistry, and immunofluorescence examination were applied. The protein presence of RIP1, but not RIP3, was increased in the mouse OA tissue and cultured chondrocytes exposed to TNF-α. Knockdown of RIP1 increased protein expression of collagen II and sex-determining region Y-box transcription factor 9, and reduced protein expression of matrix metallopeptidases 13 and a disintegrin and metalloproteinase with thrombospondin motifs 5. Inhibition of RIP1 reduced the phosphorylated NF-κB signals, decreased cell apoptosis, and restored extracellular matrix expression in cultured chondrocytes. Both RNAi and pharmacological inhibition of RIP1 decelerated the progress of OA in mice. RIP1 regulates chondrocyte apoptosis through NF-κB signaling. Inhibition of RIP1 provides a novel therapeutic approach for OA therapy.