chondrocyte apoptosis
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2022 ◽  
Vol 12 ◽  
Author(s):  
Nanxing Yi ◽  
Yilin Mi ◽  
Xiaotong Xu ◽  
Naping Li ◽  
Fan Zeng ◽  
...  

As life expectancy increases, Osteoarthritis (OA) is becoming a more frequently seen chronic joint disease. The main characteristics of OA are loss of articular cartilage, subchondral bone sclerosis, and synovial inflammation. Baicalein (Bai), a traditional Chinese medicine extracted from Scutellaria baicalensis Georgi, has been demonstrated to exert notable anti-inflammatory effects in previous studies, suggesting its potential effect in the treatment of OA. In this study, we first predicted the action targets of Bai, mapped target genes related to OA, identified potential anti-OA targets for Bai, performed gene ontology (GO) enrichment, and KEGG signaling pathway analyses of the action targets, and analyzed the molecular docking of key Bai targets. Additionally, the effect and potential mechanism of Bai against OA were verified in mouse knee OA models induced by destabilized medial meniscus (DMM) surgery. GO and KEGG analyses showed that 19 anti-OA targets were mainly involved in the response to oxidative stress, the response to hypoxia and apoptosis, and the PI3K-Akt and p53 signaling pathways. Molecular docking results indicated that BAX, BCL 2, and Caspase 3 enriched in the apoptotic signaling pathway have high binding affinity with Bai. Validation experiments showed that Bai can significantly attenuate the loss of articular cartilage (OARSI score), suppress synovial inflammation (synovitis score), and ameliorate subchondral bone resorption measured by micro-CT. In addition, Bai notably inhibited the expression of apoptosis-related proteins in articular cartilage (BAX, BCL 2, and Caspase 3). By combining network pharmacology with experimental validation, our study identifies and verifies the importance of the apoptotic signaling pathway in the treatment of OA by Bai. Bai may have promising application and potential therapeutic value in OA treatment.


2022 ◽  
Author(s):  
Jun Zhang ◽  
Yu Hu ◽  
Zihan Wang ◽  
Xuelian Wu ◽  
Chun Yang ◽  
...  

Abstract Background: It remains unclear whether hypoxic conditions affect apoptosis and contribute to degradation of cartilaginous tissues in osteoarthritis (OA) lesions. In this study, we hypothesized that hypoxic conditions induced the accumulation of hypoxia-inducible factor (HIF) and activated apoptosis to contribute to OA cartilage degeneration in vivo.Methods: Malocclusion stress was applied for 2 weeks, 4 weeks and 8 weeks to induce an OA-like lesion animal model (OD) in rats. Histological analysis was performed by H&E staining and safranin O/fast green staining. The expression levels of protein in condylar cartilage were examined by immunostaining to evaluate cartilage degeneration.Results: We found apparent histological phenotypes associated with degeneration in the occlusion disorder stress (OD) group. The OD group at 4 weeks and 8 weeks had obviously reduced expression of Acan and Col II in cartilage. In contrast, the OD groups had higher levels of Col X, ADAMTS5 and MMP13 in the condylar cartilage than the control group. Moreover, the OD group cartilage had prominent degenerative changes with reduced levels of HIF1α and increased levels of HIF2α and the apoptosis factor Caspase3 in condylar cartilage at 8 weeks.Occlusion disorder stress results in cartilage degeneration. HIF1α and HIF2α are involved in temporomandibular joint (TMJ) cartilage homeostasis by regulating chondrocyte apoptosis, which contributes to TMJ cartilage degeneration. Conclusion: Thus, abnormal hypoxic conditions inducing opposite expression patterns of HIF1α and HIF2α could be involved in the pathogenesis of condylar cartilage degeneration. HIF2α may provide a potential negative feedback mechanism for HIF1α during cartilage damage.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Sujeong Park ◽  
In-Jeoung Baek ◽  
Ji Hyun Ryu ◽  
Churl-Hong Chun ◽  
Eun-Jung Jin

AbstractHere, in Ppara−/− mice, we found that an increased DNL stimulated the cartilage degradation and identified ACOT12 as a key regulatory factor. Suppressed level of ACOT12 was observed in cartilages of OA patient and OA-induced animal. To determine the role and association of ACOT12 in the OA pathogenesis, we generated Acot12 knockout (KO) (Acot12−/−) mice using RNA-guided endonuclease. Acot12−/− mice displayed the severe cartilage degradation with the stimulation of matrix MMPs and chondrocyte apoptosis through the accumulation of acetyl CoA. Delivery of acetyl CoA-conjugated chitosan complex into cartilage stimulated DNL and cartilage degradation. Moreover, restoration of ACOT12 into human OA chondrocytes and OA-induced mouse cartilage effectively rescued the pathophysiological features of OA by regulating DNL. Taken together, our study suggested ACOT12 as a novel regulatory factor in maintaining cartilage homeostasis and targeting ACOT12 could contribute to developing a new therapeutic strategy for OA.


Gerontology ◽  
2022 ◽  
pp. 1-11
Author(s):  
Chengyuan Zhang ◽  
Ye Lu ◽  
Feng Yuan ◽  
Shilin Jiang

<b><i>Objective:</i></b> CircCCDC66 is involved in cancer progression, but its role in osteoarthritis (OA) remains unknown. This study was carried out to explore the biological role of circCCDC66 in OA and its underlying mechanism. <b><i>Methods:</i></b> The expression levels of miR-3622b-5p and circCCDC66 in OA cartilage tissues were detected by qRT-PCR. Cell Counting Kit-8 (CCK8) and flow cytometry were used to detect the chondrocyte viability and apoptosis. The expression of chondrocyte inflammatory factors (IL-6 and TNF-α) was measured by ELISA. The target genes of circCCDC66 and miR-3622b-5p were analyzed by bioinformatics analysis and luciferase reporter gene assay. The relationship between circCCDC66 and miR-3622b-5p was analyzed by bioinformatics analysis and luciferase reporter gene assay. <b><i>Results:</i></b> It was found that circCCDC66 expression in OA cartilage tissues was upregulated. CircCCDC66 overexpression inhibited proliferation and promoted apoptosis of chondrocytes and increased IL-6 and TNF-α levels in chondrocytes. miR-3622b-5p was predicted to be a downstream target gene of circCCDC66, and circCCDC66 overexpression inhibited miR-3622b-5p expression in chondrocytes. Moreover, miR-3622b-5p expression was downregulated in OA cartilage tissues. miR-3622b-5p overexpression increased chondrocyte proliferation, inhibited chondrocyte apoptosis, and enhanced the expression of IL-6 and TNF-α in chondrocytes. In addition, circCCDC66 overexpression enhanced SIRT3 expression in chondrocytes, while miR-3622b-5p overexpression inhibited SIRT3 expression in chondrocytes. <b><i>Conclusion:</i></b> CircCCDC66 promoted OA chondrocyte apoptosis by regulating the miR-3622b-5p/SIRT3 axis. CircCCDC66 may be a new therapeutic target of OA.


2021 ◽  
Author(s):  
pengfei xue ◽  
Guanyin Wu ◽  
huricha jin ◽  
jiawei jiang ◽  
Mo zhang ◽  
...  

Abstract Facet joint osteoarthritis (FJOA) is one of the common causes of low back pain, but the molecular mechanism is still unclear. Previous studies have found that P2X7 receptor has been proved to play an important role in skeletal and joint diseases. The purpose of this study was to explore the role of A740003, selective P2X7R antagonist, in the development of FJOA. Our study found that A740003 can inhibit the expression of P2X7R in OA chondrocytes. It can lead to anti-inflammatory and anti-apoptotic effects in primary chondrocytes by IL-1β/BzATP. Our results imply that decreased P2X7R can reverse chondrocyte apoptosis and prevent extracellular matrix degradation by NF-KB pathway. Moreover, in our present work, we found that A740003 inhibit the abrrently activation of NF-KB pathway by preventing the activated P65 translocation to nucleus. Our results indicate that P2X7R is a therapeutic target for the treatment of FJOA, and that A740003 could be a therapeutic candidate for this clinical application.


2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Kai Jiang ◽  
Ting Jiang ◽  
Yang Chen ◽  
Xinzhan Mao

Osteoarthritis (OA) had a high incidence in people over 65 years old, and there is currently no drug that could completely cure it. This study is aimed at studying the role of exosomes in regulating glutamine metabolism in the treatment of OA. First, we identified the exosomes extracted from the mouse OA model’s bone marrow mesenchymal stem cells (MSC). In vitro, compared with the control group, the cell apoptosis in the OA group increased, while the cell proliferation of the OA group was suppressed. After exosomal treatment, cell apoptosis and cell proliferation were reversed. Inflammatory factors (TNFα, IL-6), glutamine metabolic activity-related proteins (c-MYC, GLS1), glutamine, and GSH/GSSG were increased in the OA group. The overexpression of c-MYC reduced the therapeutic effect of exosomes. At the same time, we found that chondrocyte functional factors (collagen II, Aggrecan) were improved under the treatment of exosomes. However, oe-c-MYC reversed the therapeutic effect of exosomes. In vivo, we found that the running capacity of the mice in the OA group was reduced, and the cartilage tissue was severely damaged. In addition, TNFα, IL-6, and chondrocyte apoptosis increased, while the metabolism of collagen II, Aggrecan, and glutamate decreased in the OA group. After exosomal treatment, the mice’s exercise capacity, tissue damage, inflammation, and chondrocyte function were improved, and glutamate metabolism was increased. This study showed that exosomes regulated the level of chondrocyte glutamine metabolism by regulating c-MYC, thereby alleviating OA.


2021 ◽  
Author(s):  
Tianwen Sun ◽  
Fei Wang ◽  
Gaojian Hu ◽  
Zhizhou Li

Abstract Purpose: Salvianolic acid B (Sal B) possesses strong anti-inflammatory and antioxidant activity. This study aims to explore the underlying mechanism of Sal B to improve the obesity-related osteoarthritis (OA). Methods: C57BL/6J male mice were fed with a standard diet, a high fat diet (HFD), or HFD with Sal B (25 mg/kg), and mouse body weights and osteoarticular inflammatory factor levels were examined. Mouse chondrogenic cell line ATDC5 were transfected with lncRNA KCNQ1 overlapping transcript 1 small hairpin RNA (KCNQ1OT1 shRNA), miR-128-3p mimic or Sirtuin-1 small interfering RNA (SIRT1 siRNA), then stimulated with Palmitic acid (PA) followed by the treatment of Sal B. Then, inflammatory response, apoptosis, and autophagy of ATDC5 cells in different groups were detected. Results: Sal B reduced body weight, decreased the levels of inflammatory markers, and improved cartilage damage in OA mice. KCNQ1OT1 was downregulated in OA mice and PA- stimulated ATDC5 cells. Sal B protected ATDC5 cells against PA-mediated inflammation, apoptosis, and the inhibition of autophagy, while knockdown of KCNQ1OT1 reversed these results. KCNQ1OT1 was found to be functioned as a ceRNA to bind and downregulate the expression of miR-128-3p that was upregulated in PA-induced cells. Furthermore, SIRT1 was verified as a target of miR-128-3p. MiR-128-3p overexpression reversed the effects of Sal B on inflammatory response, apoptosis, and autophagy in PA-stimulated cells, and knockdown of SIRT1 displayed similar results. Conclusion: Sal B exerted a chondroprotective effect by upregulating KCNQ1OT1, which indicates Sal B can used for a therapeutic agent in obesity-related OA.


2021 ◽  
Vol 12 ◽  
Author(s):  
Zheng Tian ◽  
Xinan Zhang ◽  
Mingli Sun

Osteoarthritis (OA) is a common degenerative joint disease and is a leading cause of disability and reduced quality of life worldwide. There are currently no clinical treatments that can stop or slow down OA. Drugs have pain-relieving effects, but they do not slow down the course of OA and their long-term use can lead to serious side effects. Therefore, safe and clinically appropriate long-term treatments for OA are urgently needed. Autophagy is an intracellular protective mechanism, and targeting autophagy-related pathways has been found to prevent and treat various diseases. Attenuation of the autophagic pathway has now been found to disrupt cartilage homeostasis and plays an important role in the development of OA. Therefore, modulation of autophagic signaling pathways mediating cartilage homeostasis has been considered as a potential therapeutic option for OA. Phytochemicals are active ingredients from plants that have recently been found to reduce inflammatory factor levels in cartilage as well as attenuate chondrocyte apoptosis by modulating autophagy-related signaling pathways, which are not only widely available but also have the potential to alleviate the symptoms of OA. We reviewed preclinical studies and clinical studies of phytochemicals mediating autophagy to regulate cartilage homeostasis for the treatment of OA. The results suggest that phytochemicals derived from plant extracts can target relevant autophagic pathways as complementary and alternative agents for the treatment of OA if subjected to rigorous clinical trials and pharmacological tests.


Author(s):  
Chongzhi Pan ◽  
Wenzhou Huang ◽  
Qi Chen ◽  
Jiu Xu ◽  
Guoyu Yao ◽  
...  

Purpose: Extracellular Vesicles (EVs) derived from hMSCs, have the potential to alleviate cartilage damage and inflammation. We aimed to explore the effects of EVs derived from lncRNA malat‐1-overexpressing human mesenchymal stem cells (hMSCs) on chondrocytes.Material and Methods: hMSCs-derived Extracellular Vesicles (hMSCs-EVs) were identified by transmission electron microscopy and western blot. We used a Sprague-Dawley (SD) rat model of CollagenaseⅡ-induced osteoarthritis (OA) as well as IL-1β-induced OA chondrocytes. Lentiviral vectors were used to overexpress lncRNA malat‐1 in hMSCs. Chondrocyte proliferation, inflammation, extracellular matrix degradation, and cell migration were measured by Edu staining, ELISA, western blot analysis, and transwell assay. Chondrocyte apoptosis was evaluated by flow cytometry, Hoechst 33342/PI Staining, and western blot. Safranine O-fast green (S-O) staining and HE staining were used to assess morphologic alterations of the rat knee joint.Results: hMSCsmalat−1-EVs decreased MMP-13, IL-6, and Caspase-3 expression in IL-1β-induced OA chondrocytes. Moreover, hMSCsmalat−1-EVs promoted chondrocyte proliferation and migration, suppressed apoptosis, and attenuated IL-1β-induced chondrocyte injury. Our animal experiments suggested that hMSCsmalat−1-EVs were sufficient to prevent cartilage degeneration.Conclusion: Our findings show that lncRNA malat-1from hMSCs‐delivered EVs can promote chondrocyte proliferation, alleviate chondrocyte inflammation and cartilage degeneration, and enhance chondrocyte repair. Overall, hMSCsmalat−1-EVs might be a new potential therapeutic option for patients with OA.


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