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1.
Mediators Inflamm ; 2022: 1870579, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36133743

RESUMO

Osteoarthritis (OA), a chronic degenerative joint disease, always occurred in the aging population. There is evidence suggests that chondrocytes' survival, inflammation, and apoptosis play critical roles in OA pathogenesis. LMX1B has been shown to be involved in antiosteogenic function in early patterning of the calvaria. However, the role and mechanism of LMX1B in OA is not unknown. The present study observed that LMX1B was highly expressed in OA patients compared with normal patients. Besides, we found that IL-1ß increased LMX1B mRNA and protein expression in SW1353 and C28/I2 chondrocytes. LMX1B knockdown increased IL-1ß-induced cell viability and proliferation and suppressed cell apoptosis and inflammation response, including IFN-γ, TNF-α, IL-6, prostaglandin E2 (PGE2), and NO both in SW1353 and C28/I2. Furthermore, LMX1B silence inhibited MMP-3 and MMP-13 expression both in SW1353 and C28/I2 cells. Also, the activation of the NF-κB and NLRP3 signaling pathway was suppressed in LMX1B silence cells by decreasing the p-p65 and NLRP3 protein expressions. Additionally, inhibition of NF-κB by PDTC suppressed NLRP3 expression. Moreover, NLRP3 overexpression reversed the effects of LMX1B silence on chondrocytes' survival, proliferation, apoptosis, and inflammation. Finally, we confirmed that LMX1B depletion had protective effects in OA rats in vivo.


Assuntos
Condrócitos , Osteoartrite , Idoso , Animais , Apoptose/genética , Células Cultivadas , Dinoprostona/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , NF-kappa B/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Osteoartrite/metabolismo , RNA Mensageiro/metabolismo , Ratos , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Arthritis Res Ther ; 24(1): 216, 2022 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-36068644

RESUMO

BACKGROUND: Osteoarthritis (OA) is a chronic degenerative joint disease. Extracellular matrix (ECM) degradation is essential for OA progression. Previous studies have shown that circular RNAs (circRNAs) are involved in the pathological process of OA. CircPRKCH has been shown to be upregulated in OA chondrocytes. The present study was aimed to explore the roles of circPRKCH in vivo and in vitro models of OA and its underlying molecular mechanisms. METHODS: IL-1ß-induced chondrocytes and mice injected with monosodium iodoacetate were used as OA models in vitro and in vivo, respectively. RT-qPCR was performed to measure the expression of circPRKCH, miR-145, and HGF in cartilage tissues and chondrocytes. The interaction between miR-145 and circPRKCH or HGF was verified by a dual-luciferase reporter assay. Chondrocyte apoptosis, viability, and ECM-related proteins were examined by flow cytometry, MTT assay, and Western blotting, respectively. Histopathological changes were detected by HE and Safranin O-fast green staining. RESULTS: The expression of circPRKCH and HGF was increased in OA cartilage tissues and IL-1ß-treated chondrocytes, while miR-145 expression was decreased. IL-1ß induced chondrocyte apoptosis and ECM degradation in chondrocytes. Moreover, circPRKCH promoted HGF expression and activated HGF/c-MET by directly binding to miR-145. miR-145 knockdown or HGF overexpression significantly reversed circPRKCH knockdown-mediated inhibition of apoptosis and ECM degradation in IL-1ß-induced chondrocytes. Besides, miR-145 overexpression alleviated IL-1ß-induced chondrocyte apoptosis and ECM degradation by inhibiting HGF/c-MET. Finally, circPRKCH knockdown reduced ECM degradation by regulating the miR-145/HGF axis in an experimental OA model in mice. CONCLUSION: Our study demonstrated that circPRKCH promoted chondrocyte apoptosis and ECM degradation via the miR-145/HGF axis in OA, which may provide a novel target for OA treatment.


Assuntos
MicroRNAs , Osteoartrite , Animais , Apoptose/genética , Cartilagem/metabolismo , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Interleucina-1beta/metabolismo , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Osteoartrite/metabolismo
3.
J Nanobiotechnology ; 20(1): 419, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123746

RESUMO

Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into cartilage. However, the underlying biomechanisms and potential bioactivities remain oversimplified. Inspired by oxidative stress in the pathogenesis of osteoarthritis, we firstly testified the antioxidant capacity of a synthetic small molecule compound, oltipraz (OL), to the chondrocytes treated by IL-1ß. Then a functional reactive oxygen species (ROS) responsive nanocarrier, mesoporous silica nanoparticles (MSN) modified with methoxy polyethylene glycol-thioketal, was constructed. In vitro biomolecular results showed that compared with OL alone, MSN-OL could significantly activate Nrf2/HO-1 signaling pathway, which exhibited better ROS-scavenging proficiency and greater anti-apoptotic ability to protect mitochondrial membrane potential of chondrocytes. Further bioinformatics analysis revealed that MSN-OL suppressed clusters of genes associated with extracellular matrix organization, cell apoptosis and cellular response to oxidative stress. Animal experiments further confirmed the great cartilage-protecting ability of MSN-OL through upregulating the expression of Nrf2/HO-1 signaling pathway without obvious toxicity. In summary, this study provided a delivery system through ROS-responsive regulation of the therapeutic agents into chondrocytes of the cartilage, and confirmed the exact biological mechanisms of this innovative strategy.


Assuntos
Fator 2 Relacionado a NF-E2 , Osteoartrite , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Cartilagem/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Polietilenoglicóis/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/uso terapêutico
4.
J Musculoskelet Neuronal Interact ; 22(3): 393-400, 2022 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-36046996

RESUMO

OBJECTIVES: The present study aimed to identify different key genes and pathways between postmenopausal females and males by studying differentially expressed genes (DEGs). METHODS: GSE32317 and GSE55457 gene expression data were downloaded from the GEO database, and DEGs were discovered using R software to obtain overlapping DEGs. The interaction between overlapping DEGs was further analyzed by establishing the protein-protein interaction (PPI) network. Finally, GO and KEGG were used for enrichment analysis. RESULTS: 924 overlapping DEGs between postmenopausal women and men with osteoarthritis (OA) were identified, including 674 up-regulated genes and 249 down-regulated ones. And 10 hub genes were identified in the PPI network, including BMP4, KDM6A, JMJD1C, NFATC1, PRKX, SRF, ZFX, LAMTOR5, UFD1L and AMBN. The findings of the functional enrichment analysis suggested that these genes were predominantly expressed in MAPK signaling pathway as well as the Thyroid hormone signaling pathway, indicating that those two pathways may be involved in onset and disease progression of OA in postmenopausal patients. CONCLUSION: BMP4, KDM6A, JMJD1C, PRKX, ZFX and LAMTOR5 are expected to play crucial roles in disease development in postmenopausal patients and may be ideal targets or prognostic markers for the treatment of OA.


Assuntos
Biologia Computacional , Osteoartrite , Bases de Dados Genéticas , Feminino , Perfilação da Expressão Gênica , Histona Desmetilases , Humanos , Histona Desmetilases com o Domínio Jumonji , Masculino , Osteoartrite/genética , Osteoartrite/metabolismo , Oxirredutases N-Desmetilantes , Caracteres Sexuais
5.
Int J Mol Sci ; 23(17)2022 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-36077129

RESUMO

Osteoarthritis (OA) is a joint degenerative disease that most affects old age. The study of proteomics in synovial fluid (SF) has the task of providing additional elements to diagnose and predict the progress of OA. This review aims to identify the most significant biomarkers in the study of OA and to stimulate their routine use. Some of the major components of the ECM, such as proteoglycan aggrecan and decorin, were found considerably reduced in OA. Some biomarkers have proved useful for staging the temporality of OA: Periostin was found to be increased in early OA, while CRTA1 and MMPs were found to be increased in late OA. In its natural attempt at tissue regeneration, Collagen III was found to be increased in early OA while decreased in late OA. Some molecules studied in other areas, such as ZHX3 (oncological marker), LYVE1, and VEGF (lymph and angiogenesis markers), also have been found to be altered in OA. It also has been recorded that alteration of the hormonal pathway, using a dosage of PPAR-γ and RETN, can influence the evolution of OA. IL-1, one of the most investigated biomarkers in OA-SF, is not as reliable as a target of OA in recent studies. The study of biomarkers in SF appears to be, in combination with the clinical and radiological aspects, an additional weapon to address the diagnosis and staging of OA. Therefore, it can guide us more appropriately towards the indication of arthroplasty in patients with OA.


Assuntos
Osteoartrite , Líquido Sinovial , Biomarcadores/metabolismo , Humanos , Osteoartrite/diagnóstico , Osteoartrite/metabolismo , Medicina de Precisão , Proteoma/metabolismo , Líquido Sinovial/metabolismo
6.
Cells ; 11(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36078169

RESUMO

Aberrant subchondral bone architecture is a crucial driver of the pathological progression of osteoarthritis, coupled with increased sensory innervation. The sensory PGE2/EP4 pathway is involved in the regulation of bone mass accrual by the induction of differentiation of mesenchymal stromal cells. This study aimed to clarify whether the sensory PGE2/EP4 pathway induces aberrant structural alteration of subchondral bone in osteoarthritis. Destabilization of the medial meniscus (DMM) using a mouse model was combined with three approaches: the treatment of celecoxib, capsaicin, and sensory nerve-specific prostaglandin E2 receptor 4 (EP4)-knockout mice. Cartilage degeneration, subchondral bone architecture, PGE2 levels, distribution of sensory nerves, the number of osteoprogenitors, and pain-related behavior in DMM mice were assessed. Serum and tissue PGE2 levels and subchondral bone architecture in a human sample were measured. Increased PGE2 is closely related to subchondral bone's abnormal microstructure in humans and mice. Elevated PGE2 concentration in subchondral bone that is mainly derived from osteoblasts occurs in early-stage osteoarthritis, preceding articular cartilage degeneration in mice. The decreased PGE2 levels by the celecoxib or sensory denervation by capsaicin attenuate the aberrant alteration of subchondral bone architecture, joint degeneration, and pain. Selective EP4 receptor knockout of the sensory nerve attenuates the aberrant formation of subchondral bone and facilitates the prevention of cartilage degeneration in DMM mice. Excessive PGE2 in subchondral bone caused a pathological alteration to subchondral bone in osteoarthritis and maintaining the physiological level of PGE2 could potentially be used as an osteoarthritis treatment.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Capsaicina/farmacologia , Cartilagem Articular/metabolismo , Celecoxib/farmacologia , Celecoxib/uso terapêutico , Dinoprostona/metabolismo , Humanos , Camundongos , Camundongos Knockout , Osteoartrite/metabolismo , Dor/metabolismo
7.
Cells ; 11(17)2022 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-36078172

RESUMO

BACKGROUND: The disruption of joint homeostasis is a critical event during the process of joint injury in osteoarthritis (OA). As regulatory molecules, microRNAs (miRNAs) can be released from secretory cells and delivered to recipient cells through extracellular vesicles (EVs), thereby playing an important role in regulating joint homeostasis. We hypothesized that the fibroblast-like synoviocytes (FLSs) in healthy joints could release EVs enriched in miRNAs that can maintain joint homeostasis by regulating the signal transduction pathways in the joints, whereby the articular cartilage (AC) is protected from degeneration, and OA progression is delayed. METHODS: Via high-throughput sequencing and qPCR, we found that miR-150-3p was enriched in the circulating EVs in healthy rats. Next, we established an in vitro cell model in which chondrocytes were cultured with (i) FLSs transfected with miR-150-3p mimics or (ii) EVs released by FLSs (FLS-EVs) inside the healthy synovial membrane (SM). The transportation mechanism from FLSs to chondrocytes was studied using the EV inhibitor GW4869, and the FLSs were transfected with a miR-150-3p mimic or inhibitor. To assess the therapeutic effect of miR-150-3p-carrying EVs (EVs-150) in vivo, healthy FLS-derived EVs (H-FLS-EVs) were injected into the tail vein of rats with OA at various stages of the pathogenesis and evaluated for the progression of OA. RESULTS: The chondrocytes could uptake fluorescent-labeled miR-150-3p mimics and FLS-EVs, and GW4869 suppressed this uptake. The overexpression of miR-150-3p could significantly reduce the concentrations of pro-inflammatory cytokines in the cell culture medium and the expression of the miR-150-3p target T cell receptor-interacting molecule 14 (Trim14), as well as the innate immune-related factors, including nuclear factor kappa B (NF-κB) and interferon-ß (IFN-ß). Similarly to the in vitro findings, the miR-150-3p level in the serum EVs was significantly upregulated among the EV-treated rats. In the AC of the OA rat model injected with H-FLS-EVs, the joint degeneration was suppressed, and Type II collagen (COLII) and aggrecan (ACAN) were significantly upregulated, whereas the innate immune-related factors Trim14, NF-κB, and IFN-ß were downregulated compared with the levels in the untreated OA rats. Notably, the suppression of joint degeneration was more significant when H-FLS-EVs were administered at the early stages of OA rather than the late stages. CONCLUSION: H-FLS-EVs protect chondrocyte function and maintain joint homeostasis by modulating the innate immune response by suppressing the Trim14/NF-κB/IFNß axis. These effects are achieved through the EV-mediated transport of miR-150-3p from the FLSs to the chondrocytes. Our findings show that EV-mediated miR-150-3p can be used to suppress OA, thus providing a novel therapeutic strategy. Additionally, the EV-mediated miR-150-3p transport may also serve as a potential biomarker in the diagnosis, treatment, and prognosis of OA.


Assuntos
Vesículas Extracelulares , MicroRNAs , Osteoartrite , Animais , Vesículas Extracelulares/metabolismo , Homeostase , MicroRNAs/genética , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Ratos
8.
Oxid Med Cell Longev ; 2022: 1135827, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36071864

RESUMO

Osteoarthritis (OA) is a frequently observed condition in aged people. OA cartilage is characterized by chondrocyte apoptosis, chondrocyte inflammation, and hyperactive catabolism of extracellular matrix. However, the specific molecular mechanisms remain unclear. Recent data has shown that Angptl4, a multifunctional cytokine, is involved in the regulation of inflammatory and apoptosis responses in different tissues. This study is aimed at defining the role of Angptl4 in the development of OA. We employed X-ray analysis, safranin O-fast green (S-O) staining, and hematoxylin staining to evaluate histomorphological characteristics in the knee joint of mice. Real-time quantitative polymerase chain reaction, Western blot assays, immunofluorescence staining, and enzyme-linked immunosorbent assays (ELISA) were performed to analyze the changes in gene and protein expression. Mechanically, our data demonstrated that Angptl4 knockdown improved the degradation of extracellular matrix and reduced TNF-α-mediated chondrocyte inflammation and apoptosis by suppressing sirtuin 1/NF-κB signaling pathway. In addition, animal studies showed that the suppression of Angptl4 expression might alleviate OA development. In conclusion, our findings revealed the underlying mechanisms of Angptl4 regulation in chondrocytes and its potential value in the treatment of OA.


Assuntos
Proteína 4 Semelhante a Angiopoietina , NF-kappa B , Osteoartrite , Proteína 4 Semelhante a Angiopoietina/genética , Animais , Apoptose , Células Cultivadas , Matriz Extracelular/metabolismo , Inativação Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Camundongos , NF-kappa B/metabolismo , Osteoartrite/genética , Osteoartrite/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo
9.
Int J Mol Med ; 50(5)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36102306

RESUMO

Osteoarthritis (OA) is the most common degenerative disease affecting the joints, and inflammation appears to play a critical role in the initiation and progression of OA. Caffeic acid phenethyl ester (CAPE), a natural flavonoid compound, has anti­inflammatory and antioxidant functions. However, its anti­inflammatory effects on OA and the underlying mechanisms of action of CAPE in the treatment of OA remain elusive. Therefore, the present study investigated the anti­inflammatory effects of CAPE on IL­1ß­stimulated chondrocytes in vitro and surgically induced rat models of OA in vivo. In vitro, CAPE reduced the expression of inducible nitric oxide synthase and cyclooxygenase­2 in IL­1ß­stimulated chondrocytes, as well as the extracellular secretion of nitric oxide and prostaglandin E2 in the cell culture supernatants. In addition, CAPE attenuated the degradation of extracellular matrix by increasing the expression of aggrecan and collagen II, and decreasing the expression of MMP3, MMP13 and a disintegrin and metalloproteinase with thrombospondin motif­5. Furthermore, CAPE attenuated NF­κB signaling and activated the nuclear factor erythroid 2­related factor 2/heme oxygenase­1 signaling pathway in IL­1ß­stimulated chondrocytes. In vivo, CAPE protected cartilage from destruction and delayed the progression of OA in rats. Taken together, the findings of the present study indicated that CAPE may be a potential therapeutic agent for the prevention or treatment of OA.


Assuntos
NF-kappa B , Osteoartrite , Animais , Anti-Inflamatórios/farmacologia , Ácidos Cafeicos , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Álcool Feniletílico/análogos & derivados , Ratos , Transdução de Sinais
10.
Molecules ; 27(17)2022 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-36080383

RESUMO

High molecular weight hyaluronic acids (HMW-HAs) have been used for the palliative treatment of osteoarthritis (OA) for decades, but the pharmacological activity of HA fragments has not been fully explored due to the limited availability of structurally defined HA fragments. In this study, we synthesized a series glycosides of oligosaccharides of HA (o-HAs), hereinafter collectively referred to as o-HA derivatives. Their effects on OA progression were examined in a chondrocyte inflammatory model established by the lipopolysaccharide (LPS)-challenged ATDC5 cells. Cell Counting Kit-8 (CCK-8) assays and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) showed that o-HA derivatives (≤100 µg/mL) exhibited no cytotoxicity and pro-inflammatory effects. We found that the o-HA and o-HA derivatives alleviated LPS-induced inflammation, apoptosis, autophagy and proliferation-inhibition of ATDC5 cells, similar to the activities of HMW-HAs. Moreover, Western blot analysis showed that different HA derivatives selectively reversed the effects of LPS on the expression of extracellular matrix (ECM)-related proteins (MMP13, COL2A1 and Aggrecan) in ATDC5 cells. Our study suggested that o-HA derivatives may alleviate LPS-induced chondrocyte injury by reducing the inflammatory response, maintaining cell proliferation, inhibiting apoptosis and autophagy, and decreasing ECM degradation, supporting a potential oligosaccharides-mediated therapy for OA.


Assuntos
MicroRNAs , Osteoartrite , Apoptose , Linhagem Celular , Sobrevivência Celular , Condrócitos , Humanos , Ácido Hialurônico/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , MicroRNAs/metabolismo , Oligossacarídeos/metabolismo , Osteoartrite/induzido quimicamente , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo
11.
Front Immunol ; 13: 901555, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36059477

RESUMO

Background: Pyruvate kinase M2 (PKM2) is an enzyme that regulates the final process of glycolysis and exists in tetrameric and dimeric forms. The dimeric form of PKM2, also known as tumour M2-PK, increases when aerobic glycolysis is augmented, a feature observed in rheumatoid arthritis (RA). We investigated whether plasma tumour M2-PK is elevated in patients with RA and whether its levels correlate with disease activity. Methods: Plasma levels of tumour M2-PK were measured for patients with RA (n=151), those with osteoarthritis (OA) (n=37), and controls (n=37). We evaluated the association between plasma tumour M2-PK and continuous variables using Pearson's correlation analysis, and multivariate logistic regression analysis to determine the association between plasma tumour M2-PK and disease activity status. Knee synovial tissue blocks from patients with RA and OA were subjected to real-time quantitative PCR (qPCR) using two different primers for PKM2 and tumour M2-PK immunohistochemical (IHC) staining. Results: The tumour M2-PK level significantly correlated with the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) (r=0.546, p<0.001) and DAS28-C-reactive protein (CRP) (r=0.589, p<0.001). Moreover, repeat testing of tumour M2-PK levels in 20 patients revealed a significant decline in tumour M2-PK levels after reduction in inflammation (p<0.001). Area under the receiver operating characteristic curve (AUROC) analysis demonstrated that upon incorporation of tumour M2-PK, ESR, and CRP, the area under the curve was 0.962 for distinguishing moderate/high from remission/low disease activity. Adjusted logistic regression also revealed that a tumour M2-PK >43.9 U/mL (OR 3.672, p=0.042) independently predicted moderate/high disease activity status. Furthermore, tumour M2-PK levels in patients with RA were significantly higher than in those with OA and controls (all p<0.001). However, no differences were found in PKM2 expression in RA and OA synovial tissues as assessed by qPCR, and IHC analysis revealed negligible tumour M2-PK expression in the synovial tissues. Conclusion: Circulating plasma tumour M2-PK levels may be a clinically useful indicator for evaluating disease activity and RA diagnosis.


Assuntos
Artrite Reumatoide , Osteoartrite , Piruvato Quinase , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/patologia , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Humanos , Neoplasias/diagnóstico , Neoplasias/patologia , Osteoartrite/diagnóstico , Osteoartrite/metabolismo , Osteoartrite/patologia , Membrana Sinovial/patologia
12.
Cells ; 11(16)2022 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-36010590

RESUMO

Glycoproteins are involved in the development of many diseases, while the type and content of N-glycoproteins in the cartilage of osteoarthritis (OA) and Kashin-Beck disease (KBD) are still unclear. This research aims to identify N-glycoproteins in knee cartilage patients with OA and KBD compared with normal control (N) adults. The cartilage samples were collected from gender- and age-matched OA (n = 9), KBD (n = 9) patients, and N (n = 9) adults. Glycoproteomics and label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) obtained N-glycoproteins of KBD and OA. A total of 594 N-glycoproteins and 1146 N-glycosylation peptides were identified. The identified data were further compared and analyzed with Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interactions (PPI). Pairwise comparison of the glycoproteins detected in the three groups showed that integrin beta-1 (ITGB1), collagen alpha-1 (II) chain (COL2A1), collagen alpha-1 (VII) chain (COL7A1), carbohydrate sulfotransferase 3 (CHST-3), carbohydrate sulfotransferase 4 (CHST-4), thrombospondin 2 (THBS2), bone morphogenetic protein 8A (BMP8A), tenascin-C (TNC), lysosome-associated membrane protein (LAMP2), and beta-glucuronidase (GUSB) were significantly differentially expressed. GO results suggested N-glycoproteins mainly belonged to protein metabolic process, single-multicellular and multicellular organism process, cell adhesion, biological adhesion, and multicellular organism development. KEGG and PPI results revealed that key N-glycoproteins were closely related to pathways for OA and KBD, such as phagosome, ECM-receptor interaction, lysosome, focal adhesion, protein digestion, and absorption. These results reflected glycoprotein expression for OA and KBD in the process of ECM degradation, material transport, cell-cell or cell-ECM interaction, and information transduction. These key significantly differentially expressed N-glycoproteins and pathways lead to the degeneration and degradation of the cartilage of OA and KBD mainly by disrupting the synthesis and catabolism of basic components of ECM and chondrocytes and interfering with the transfer of material or information. The key N-glycoproteins or pathways in this research are potential targets for pathological mechanisms and therapies of OA and KBD.


Assuntos
Cartilagem Articular , Doença de Kashin-Bek , Osteoartrite , Adulto , Cartilagem Articular/metabolismo , Cromatografia Líquida , Colágeno Tipo VII/metabolismo , Glicoproteínas/metabolismo , Humanos , Doença de Kashin-Bek/genética , Doença de Kashin-Bek/metabolismo , Doença de Kashin-Bek/patologia , Joelho , Osteoartrite/metabolismo , Espectrometria de Massas em Tandem
13.
Drug Des Devel Ther ; 16: 2627-2637, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35965964

RESUMO

Purpose: Osteoarthritis (OA) is an age-related degenerative disease associated with enhanced degradation of extracellular matrix (ECM) and decreased autophagy. Our study is aimed to explore how corosolic acid (CRA) affect cartilage ECM metabolism and the potential mechanism. Methods: Rat chondrocytes were pretreated with different concentrations of CRA (0, 2.5, 5, and 10 µM), and were stimulated with IL-1ß (10ng/mL) for 24 h, subsequently. RT-qPCR, Western blot, and immunofluorescence were used to detect the expression of genes related to ECM metabolism and explore the potential molecular mechanism. The effect of CRA on articular cartilage was observed in the surgically induced OA rat model with the method of Safranin O/Fast green and immunohistochemical staining. Results: Results showed that CRA reversed the IL-1ß-induced degradation of aggrecan and type II collagen and the high expression of MMP13 and ADAMTS5. Mechanistically, CRA enhanced autophagy through inhibiting the classical PI3K/AKT/mTOR signaling pathway. Furthermore, inhibition of autophagy partly abolished the protective effects of CRA on ECM synthesis in IL-1ß-treated chondrocytes. Correspondingly, the protective effect of CRA was also confirmed in a rat OA model. Conclusion: Herein, we demonstrate that CRA can enhance autophagy by inhibiting PI3K/AKT/mTOR signaling pathway, prevent IL-1ß-induced cartilage ECM degradation, and may be a potentially applicable candidate for the treatment of OA.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Autofagia , Condrócitos , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo , Triterpenos
14.
Int J Mol Sci ; 23(15)2022 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-35955467

RESUMO

Synovial fluid (SF) represents the primary source of nutrients of articular cartilage and is implicated in maintaining cartilage metabolism. We investigated the effects of SF, from patients with osteoarthritis (OA), rheumatoid arthritis (RA), and controls, on a pattern of microRNA (miRNA) in human OA chondrocytes. Cells were stimulated with 50% or 100% SF for 24 h and 48 h. Apoptosis and superoxide anion production were detected by cytometry; miRNA (34a, 146a, 155, 181a), cytokines, metalloproteinases (MMPs), type II collagen (Col2a1), antioxidant enzymes, B-cell lymphoma (BCL)2, and nuclear factor (NF)-κB by real-time PCR. The implication of the NF-κB pathway was assessed by the use of NF-κB inhibitor (BAY-11-7082). RA and OA SF up-regulated miR-34a, -146a, -155, -181a, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, MMP-1, MMP-13, and ADAMTs-5 gene expression, while it down-regulated Col2a1. Pathological SF also induced apoptosis, reduced viability, and decreased BCL2 mRNA, whereas it increased superoxide anions, the expression of antioxidant enzymes, p65 and p50 NF-κB. Opposite and positive results were obtained with 100% control SF. Pre-incubation with BAY-11-7082 counteracted SF effects on miRNA. We highlight the role of the SF microenvironment in regulating some miRNA involved in inflammation and cartilage degradation during OA and RA, via the NF-κB pathway.


Assuntos
Artrite Reumatoide , Cartilagem Articular , MicroRNAs , Osteoartrite , Antioxidantes/farmacologia , Artrite Reumatoide/metabolismo , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Expressão Gênica , Humanos , Interleucina-1beta/metabolismo , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
15.
Int J Mol Sci ; 23(15)2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35955795

RESUMO

Osteoarthritis (OA) is a degenerative joint disease that is characterized by inflammation of the joints, degradation of cartilage, and the remodeling of other joint tissues. Due to the absence of disease-modifying drugs for OA, current clinical treatment options are often only effective at slowing down disease progression and focus mainly on pain management. The field of tissue engineering has therefore been focusing on developing strategies that could be used not only to alleviate symptoms of OA but also to regenerate the damaged tissue. Hyaluronic acid (HA), an integral component of both the synovial fluid and articular cartilage, has gained widespread usage in developing hydrogels that deliver cells and biomolecules to the OA joint thanks to its biocompatibility and ability to support cell growth and the chondrogenic differentiation of encapsulated stem cells, providing binding sites for growth factors. Tissue-engineering strategies have further attempted to improve the role of HA as an OA therapeutic by developing diverse modified HA delivery platforms for enhanced joint retention and controlled drug release. This review summarizes recent advances in developing HA-based hydrogels for OA treatment and provides additional insights into how HA-based therapeutics could be further improved to maximize their potential as a viable treatment option for OA.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Ácido Hialurônico/química , Hidrogéis/química , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Líquido Sinovial/metabolismo
16.
Front Immunol ; 13: 936606, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967352

RESUMO

Background: Synovial macrophages play important roles in the formation and progression of osteoarthritis (OA). This study aimed to explore the biological and clinical significance of macrophage-associated genes (MAGs) in OA. Methods: The OA synovial gene expression profiles GSE89408 and GSE82107 were obtained from the GEO database. Single-sample gene set enrichment analysis (ssGSEA) and GSEA were employed to decipher differences in immune infiltration and macrophage-associated biological pathways, respectively. Protein-protein interaction (PPI) network analysis and machine learning were utilized to establish a macrophage-associated gene diagnostic signature (MAGDS). RT-qPCR was performed to test the expression of key MAGs in murine models. Results: OA synovium presented high levels of immune infiltration and activation of macrophage-associated biological pathways. A total of 55 differentially expressed MAGs were identified. Using PPI analysis and machine learning, a MAGDS consisting of IL1B, C5AR1, FCGR2B, IL10, IL6, and TYROBP was established for OA diagnosis (AUC = 0.910) and molecular pathological evaluation. Patients with high MAGDS scores may possess higher levels of immune infiltration and expression of matrix metalloproteinases (MMPs), implying poor biological alterations. The diagnostic value of MAGDS was also validated in an external cohort (AUC = 0.886). The expression of key MAGs was validated in a murine model using RT-qPCR. Additionally, a competitive endogenous RNA network was constructed to reveal the potential posttranscriptional regulatory mechanisms. Conclusions: We developed and validated a MAGDS model with the ability to accurately diagnose and characterize biological alterations in OA. The six key MAGs may also be latent targets for immunoregulatory therapy.


Assuntos
Redes Reguladoras de Genes , Osteoartrite , Animais , Perfilação da Expressão Gênica , Humanos , Macrófagos/metabolismo , Camundongos , Osteoartrite/diagnóstico , Osteoartrite/genética , Osteoartrite/metabolismo , Membrana Sinovial/patologia
17.
Int Immunopharmacol ; 111: 109085, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35952515

RESUMO

As a degenerative disease, the pathogenesis and treatment of osteoarthritis (OA) are still being studied. The prevailing view is that articular cartilage dysfunction plays an essential role in the development of osteoarthritis. Similarly, dynamic bone remodeling dramatically influences the development of osteoarthritis. The inflammatory response is caused by the overexpression of inflammatory factors, among which tumor necrosis factor-α is one of the main causes of OA, and its sources include the secretion of chondrocytes themselves and osteoclast secretion of subchondral bone. Moreover, TNF-α-induced activation of RIP1, RIP3, and MLKL has been shown to play an important role in cell necroptosis and inflammatory responses. In vitro, AZ-628 alleviates chondrocyte inflammation and necroptosis by inhibiting the NF-κB signaling pathway and RIP3 activation instead of RIP1 activation. AZ-628 also reduces osteoclast activity, proliferation and differentiation, and release of inflammatory substances by inhibiting autophagy, MAPK, and NF-κB pathways. Similarly, the in vivo study demonstrated that AZ-628 could inhibit chondrocyte breakdown and lower osteoclast formation and bone resorption, thereby slowing down subchondral bone changes induced by dynamic bone remodeling and reversing the progression of osteoarthritis in mice. The results of this study indicate that AZ-628 could be used to treat OA byinhibiting chondrocyte necroptosis and regulating osteoclast formation.


Assuntos
Condrócitos , Osteoartrite , Animais , Condrócitos/metabolismo , Camundongos , NF-kappa B/metabolismo , Necroptose , Osteoartrite/metabolismo , Osteoclastos/metabolismo , Quinazolinas , Fator de Necrose Tumoral alfa/metabolismo
18.
Int Immunopharmacol ; 111: 109129, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35961266

RESUMO

Osteoarthritis (OA) is the most common arthritis, and is characterized by inflammation and cartilage degradation. Chicoric acid (CA), a bioactive caffeic acid derivative isolated from the root of Taraxacum mongolicumHand. - Mazz., has been reported to have anti-inflammatory effects. However, the therapeutic effects of CA on chondrocyte inflammation remain unknown. Our study aimed to explore the effect of CA on OA both in vivo and in vitro. In vitro, CA treatment significantly suppressed the overproduction of nitric oxide (NO), prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), and IL-12 in tumor necrosis factor alpha (TNF-α)-induced human C28/I2 chondrocytes. Moreover, CA attenuated TNF-α induced degradation of the extracellular matrix (ECM) by upregulating the expression of collagen Ⅱ and aggrecan, and downregulating ADAMTS-5 and matrix metalloproteinases (MMPs). Additionally, CA treatment inhibited apoptosis in C28/I2 cells by upregulating of Bcl-2 levels, downregulating Bax and ROS levels, and activating the Nrf2/HO-1 pathway. Mechanistically, CA exerted an anti-inflammatory effect by inhibiting the PI3K/AKT and NF-κB signaling pathways, enhancing Nrf-2/HO-1 to limit the activation of NF-κB. In vivo experiments also proved the therapeutic effects of CA on OA in rats. These findings indicate that CA may become a new drug for the treatment of OA.


Assuntos
NF-kappa B , Osteoartrite , Animais , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Apoptose , Ácidos Cafeicos , Condrócitos , Humanos , Inflamação/tratamento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Osteoartrite/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais , Succinatos , Fator de Necrose Tumoral alfa/metabolismo
19.
Biomed Pharmacother ; 154: 113551, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35988424

RESUMO

Endoplasmic reticulum stress (ERS) has been identified to be an important factor leading to chondrocyte apoptosis in osteoarthritis (OA). Previous studies have confirmed that Achyranthes bidentata polysaccharides (ABPS) can inhibit chondrocyte apoptosis; however, the mechanism of action of ABPS on chondrocyte ERS remains unclear. Thus in this study, we aim to investigate whether ABPS could inhibit OA-associated chondrocyte apoptosis by regulating ERS, especially by observing the relationship between the lncRNA NEAT1 and miR-377-3p, to explore further the protective mechanism of ABPS in OA. In vitro and in vivo experiments showed that ABPS inhibited chondrocyte ERS by regulating the expression of lncRNA NEAT1 and miR-377-3p. Moreover, both lncRNA NEAT1 silencing and miR-377-3p inhibition could attenuate the therapeutic effect of ABPS on ERS. Dual-luciferase results indicated that miR-377-3p targets the lncRNA NEAT1 gene in mouse chondrocytes. Therefore, we concluded that ABPS could inhibit thapsigargin (TG)-induced chondrocyte ERS through the lncRNA NEAT1/miR-377-3p axis.


Assuntos
Achyranthes , MicroRNAs , Osteoartrite , RNA Longo não Codificante , Animais , Apoptose , Condrócitos/metabolismo , Estresse do Retículo Endoplasmático , Camundongos , MicroRNAs/metabolismo , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/metabolismo , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , RNA Longo não Codificante/metabolismo
20.
Aging Cell ; 21(9): e13698, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35996812

RESUMO

It is known that chondrocytes from joints with osteoarthritis (OA) exhibit high levels of DNA damage, but the degree to which chondrocytes accumulate DNA damage during "normal aging" has not been established. The goal of this study was to quantify the DNA damage present in chondrocytes obtained from cadaveric donors of a wide age range, and to compare the extent of this damage to OA chondrocytes. The alkaline comet assay was used to measure the DNA damage in normal cartilage from the ankle (talus) and the knee (femur) of cadaveric donors, as well as in OA chondrocytes obtained at the time of total knee replacement. Chondrocytes from younger donors (<45 years) had less DNA damage than older donors (>70 years) as assessed by the percentage of DNA in the comet "tail". In donors between 50 and 60 years old, there was increased DNA damage in chondrocytes from OA cartilage as compared to cadaveric. Talar chondrocytes from 23 donors between the ages of 34 and 78 revealed a linear increase in DNA damage with age (R2  = 0.865, p < 0.0001). A "two-tailed" comet assay was used to demonstrate that most of the accumulated damage is in the form of strand breaks as opposed to alkali-labile base damage. Chondrocytes from young donors required 10 Gy irradiation to recapitulate the DNA damage present in chondrocytes from older donors. Given the potential for DNA damage to contribute to chondrocyte dysfunction and senescence, this study supports the investigation of mechanisms by which hypo-replicative cell types accumulate high levels of damage.


Assuntos
Cartilagem Articular , Osteoartrite , Adulto , Idoso , Envelhecimento/genética , Cadáver , Cartilagem Articular/metabolismo , Células Cultivadas , Condrócitos/metabolismo , Ensaio Cometa , Dano ao DNA/genética , Humanos , Pessoa de Meia-Idade , Osteoartrite/genética , Osteoartrite/metabolismo
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