Inhibition of PERK Signaling Prevents Against Glucocorticoid-induced Endotheliocyte Apoptosis and Osteonecrosis of the Femoral Head.
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ABSTRACT:
SUBMITTER: Gao Y
PROVIDER: S-EPMC6990927 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Long-term use of glucocorticoids (GCs) is known to be a predominant cause of osteonecrosis of the femoral head (ONFH). Moreover, GCs can mediate apoptosis of various cell types by exaggerating oxidative stress. We have previously found that Cortistatin (CST) antagonizes oxidative stress and improves cell apoptosis in several conditions. In this study, we detected that the CST expression levels were diminished in patients with ONFH compared with femoral neck fracture (FNF). In addition, a GC-induced rat ONFH model was established, which impaired bone quality in the femoral head. Then, administration of CST attenuated these ONFH phenotypes. Furthermore, osteoblast and endothelial cells were cultured and stimulated with dexamethasone (Dex) in the presence or absence of recombinant CST. As a result, Dex induced impaired anabolic metabolism of osteoblasts and suppressed tube formation in endothelial cells, while additional treatment with CST reversed this damage to the cells. Moreover, blocking GHSR1a, a well-accepted receptor of CST, or blocking the AKT signaling pathway largely abolished the protective function of CST in Dex-induced disorder of the cells. Taken together, we indicate that CST has the capability to prevent GC-induced apoptosis and metabolic disorder of osteoblasts in the pathogenesis of ONFH via the GHSR1a/AKT signaling pathway.
| S-EPMC10817896 | biostudies-literature
Project description:Inflammation is a contributing factor in osteocyte apoptosis, which is strongly associated with the development of glucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH). Curcumin is a naturally derived drug that regulates immunity and inhibits inflammation. This study aimed to examine the capacity of curcumin to prevent osteocyte apoptosis and GA-ONFH, while elucidating possible mechanisms of action. C57/BL6 female mice were divided into control, GA-ONFH, and curcumin-treated GA-ONFH groups. We determined the effect of curcumin on the polarization of RAW264.7 and the apoptosis of MLO-Y4 cells. We found that curcumin reduced the infiltration of M1-type macrophages in the femoral heads and alleviated systemic inflammation in GA-ONFH models. Additionally, curcumin decreased the apoptosis of osteocytes in the femoral heads and the ratio of GA-ONFH in mice. Further, in vitro curcumin intervention inhibited M1-type polarization via the Janus kinase1/2-signal transducer and activator of transcription protein1 (JAK1/2-STAT1) pathway. Taken together, this study demonstrates that curcumin is effective in preventing osteocyte apoptosis and the development of GA-ONFH in a mouse model. Curcumin prevents inflammatory-mediated apoptosis of osteocytes in part through inhibition of M1 polarization through the JAK1/2-STAT1 pathway. These findings provide novel insights as well as a potential preventive agent for GA-ONFH. This article is protected by copyright. All rights reserved.
| S-EPMC7496963 | biostudies-literature
Project description:Glucocorticoids (GCs) are used in treating viral infections, acute spinal cord injury, autoimmune diseases, and shock. Several patients develop GC-induced osteonecrosis of the femoral head (ONFH). However, the pathogenic mechanisms underlying GC-induced ONFH remain poorly understood. GC-directed bone marrow mesenchymal stem cells (BMSCs) fate is an important factor that determines GC-induced ONFH. At high concentrations, GCs induce BMSC apoptosis by promoting oxidative stress. In the present study, we aimed to elucidate the molecular mechanisms that relieve GC-induced oxidative stress in BMSCs, which would be vital for treating ONFH. The endocannabinoid system regulates oxidative stress in multiple organs. Here, we found that monoacylglycerol lipase (MAGL), a key molecule in the endocannabinoid system, was significantly upregulated during GC treatment in osteoblasts both in vitro and in vivo. MAGL expression was positively correlated with expression of the NADPH oxidase family and apoptosis-related proteins. Functional analysis showed that MAGL inhibition markedly reduced oxidative stress and partially rescued BMSC apoptosis. Additionally, in vivo studies indicated that MAGL inhibition effectively attenuated GC-induced ONFH. Pathway analysis showed that MAGL inhibition regulated oxidative stress in BMSCs via the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. The expression of Nrf2, a major regulator of intracellular antioxidants, was upregulated by inhibiting MAGL. Nrf2 activation can mimic the effect of MAGL inhibition and significantly reduce GC-induced oxidative damage in BMSCs. The beneficial effects of MAGL inhibition were attenuated after the blockade of the Keap1/Nrf2 antioxidant signaling pathway. Notably, pharmacological blockade of MAGL conferred femoral head protection in GC-induced ONFH, even after oxidative stress responses were initiated. Therefore, MAGL may represent a novel target for the prevention and treatment of GC-induced ONFH.
| S-EPMC8167863 | biostudies-literature
Project description:BackgroundGlucocorticoid usage and alcohol abuse are the most widely accepted risk factors for nontraumatic osteonecrosis of femoral head (ONFH). Despite distinct etiologies between glucocorticoid-associated ONFH (GONFH) and alcohol-associated ONFH (AONFH), little is known about the differences of the microarchitectural and histomorphologic characteristics between these subtypes of ONFH.PurposesTo investigate bone microarchitecture, bone remodeling activity and histomorphology characteristics of different regions in femoral heads between GONFH and AONFH.MethodsFrom September 2015 to October 2020, 85 patients diagnosed with GONFH and AONFH were recruited. Femoral heads were obtained after total hip replacement. Femoral head specimens were obtained from 42 patients (50 hips) with GONFH and 43 patients (50 hips) with AONFH. Micro-CT was utilized to assess the microstructure of 9 regions of interest (ROIs) in the femoral head. Along the supero-inferior orientation, the femoral head was divided into necrotic region, reactive interface, and normal region; along the medio-lateral orientation, the femoral head was divided into medial region, central region and lateral region. Decalcified and undecalcified bone histology was subsequently performed to evaluate histopathological alterations and bone remodeling levels.ResultsIn the necrotic region, most of the microarchitectural parameters did not differ significantly between GONFH and AONFH, whereas both the reactive interface and normal region revealed a less sclerotic microarchitecture but a higher bone remodeling level in GONFH than AONFH. Despite similar necrotic pathological manifestations, subchondral trabecular microfracture in the necrotic region was more severe and vasculature of the reactive interface was more abundant in GONFH.ConclusionsGONFH and AONFH shared similar microarchitecture and histopathological features in the necrotic region, while GONFH exhibited a less sclerotic microarchitecture and a more active bone metabolic status in both the reactive interface and normal region. These differences between GONFH and AONFH in bone microarchitectural and histopathological characteristics might contribute to the development of disease-modifying prevention strategies and treatments for ONFH, taking into etiologies.
| S-EPMC10031038 | biostudies-literature
Project description:Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a frequently occurring type of nontraumatic osteonecrosis. A failure of the timely treatment can eventually result in the collapse of the subchondral bone structure. Luteolin (Lut), a compound extracted from Rhizoma Drynariae, is reported to possess multiple pharmacological properties including anticancer, antioxidant, antiapoptosis, and antiinflammatory properties. However, whether Lut has a protective effect on the development of GIONFH remains unclear. In this study, we evaluated the effect of Lut on Dexamethasone (Dex)-induced STAT1/caspase3 pathway in vitro and evaluated GIONFH model in vivo. In vitro, Lut inhibited the upregulation of Dex-induced phospho-STAT1, cleaved caspase9, and cleaved caspase3. In addition, Lut inhibited Dex-induced expression of Bax and cytochrome c and increased the expression of B cell lymphoma-2(Bcl-2). In vivo, Lut decreased the proportion of empty lacunae in rats with GIONFH. Taken together, these findings indicate that Lut may have therapeutic potential in the treatment of GIONFH. Further, this effect might be achieved by suppressing mitochondrial apoptosis of osteoblasts via inhibition of STAT1 activity.
| S-EPMC7435053 | biostudies-literature
Project description:BackgroundGlucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a common disease in osteoarticular surgery, with a high disability rate, which brings great physical and mental pain and economic burden to patients. Its specific pathogenesis has not been fully demonstrated, and there is a lack of recognized effective biomarkers for earlier detection and prompt treatment. This has become an urgent clinical problem for orthopedic scholars.Materials and methodsWe downloaded the gene expression profile dataset GSE123568 from the Gene Expression Omnibus database, used STRING and Cytoscape to carry out module analysis and built a gene interaction network. The four core genes most related to GIONFH in this network were ultimately found out by precise analysis and animal experiment were then conducted for verification. In this verification process, thirty-six New Zealand white rabbits were randomly divided into blank control group, model group and drug group. Except for the blank control group, the animal model of GIONFH was established by lipopolysaccharide and methylprednisolone, while the drug group was given the lipid-lowering drugs for intervention as planned. The rabbits were taken for magnetic resonance imaging at different stages, and their femoral head specimens were taken for pathological examination, then the expression of target genes in the femoral head specimens of corresponding groups was detected. Validation methods included RT-PCR and pathological examination.ResultsA total of 679 differential genes were selected at first, including 276 up-regulated genes and 403 down-regulated genes. Finally, four genes with the highest degree of correlation were screened. Animal experiment results showed that ASXL1 and BNIP3L were in low expression, while FCGR2A and TYROBP were highly expressed.ConclusionThrough animal experiments, it was confirmed that ASXL1, BNIP3L, FCGR2A and TYROBP screened from the comparative analysis of multiple genes in the database were closely related to GIONFH, which is important for early diagnosis of Glucocorticoid-induced osteonecrosis of the femoral head.
| S-EPMC9832261 | biostudies-literature
Project description:BackgroundOsteoclast hyperactivation due to the pathological overproduction of reactive oxygen species (ROS) stimulated by glucocorticoids (GCs) is one of the key drivers behind glucocorticoid-induced osteonecrosis of the femoral head (GIONFH). The insulin degrading enzyme (IDE), a conserved Zn2+ metallo-endopeptidase, facilitates the DNA binding of glucocorticoid receptor and plays a substantial role in steroid hormone-related signaling pathways. However, the potential role of IDE in the pathogenesis of GIONFH is yet undefined.MethodsIn this study, we employed network pharmacology and bioinformatics analysis to explore the impact of IDE inhibition on GIONFH with 6bK as an inhibitory agent. Further evidence was collected through in vitro osteoclastogenesis experiments and in vivo evaluations involving methylprednisolone (MPS)-induced GIONFH mouse model.ResultsEnrichment analysis indicated a potential role of 6bK in redox regulation amid GIONFH development. In vitro findings revealed that 6bK could attenuate GCs-stimulated overactivation of osteoclast differentiation by interfering with the transcription and expression of key osteoclastic genes (Traf6, Nfatc1, and Ctsk). The use of an H2DCFDA probe and subsequent WB assays introduced the inhibitory effects of 6bK on osteoclastogenesis, linked with the activation of the nuclear factor erythroid-derived 2-like 2 (Nrf2)-mediated antioxidant system. Furthermore, Micro-CT scans validated that 6bK could alleviate GIONFH in MPS-induced mouse models.ConclusionsOur findings suggest that 6bK suppresses osteoclast hyperactivity in GCs-rich environment. This is achieved by reducing the accumulation of intracellular ROS via promoting the Nrf2-mediated antioxidant system, thus implying that IDE could be a promising therapeutic target for GIONFH.
| S-EPMC11292917 | biostudies-literature
Project description:Background and Objectives. Glucocorticoid-induced osteonecrosis of the femoral head (GIONFH) is a serve complication of long-term administration of glucocorticoids. Previous experimental studies have shown that ferroptosis might be involved in the pathological process of GIONFH. The purpose of this study is to identify the ferroptosis-related genes and pathways of GIONFH by bioinformatics to further illustrate the mechanism of ferroptosis in SONFH through bioinformatics analysis. Materials and Methods. The GSE123568 mRNA expression profile dataset, including 30 GIONFH samples and 10 non-GIONFH samples, was downloaded from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were obtained from the FerrDb database. First, differentially expressed genes (DEGs) were identified between the serum samples from GIONFH cases and those from controls. Ferroptosis-related DEGs were obtained from the intersection of ferroptosis-related genes and DEGs. Only ferroptosis DEGs were used for all analyses. Then, we conducted a Kyoto encyclopedia of genome (KEGG) and gene ontology (GO) pathway enrichment analysis. We constructed a protein-protein interaction (PPI) network to screen out hub genes. Additionally, the expression levels of the hub genes were validated in an independent dataset GSE10311. Results. A total of 27 ferroptosis-related DEGs were obtained between the peripheral blood samples of GIONFH cases and non-GIONFH controls. Then, GO, and KEGG pathway enrichment analysis revealed that ferroptosis-related DEGs were mainly enriched in the regulation of the apoptotic process, oxidation-reduction process, and cell redox homeostasis, as well as HIF-1, TNF, FoxO signaling pathways, and osteoclast differentiation. Eight hub genes, including TLR4, PTGS2, SNCA, MAPK1, CYBB, SLC2A1, TXNIP, and MAP3K5, were identified by PPI network analysis. The expression levels of TLR4, TXNIP and MAP3K5 were further validated in the dataset GSE10311. Conclusion. A total of 27 ferroptosis-related DEGs involved in GIONFH were identified via bioinformatics analysis. TLR4, TXNIP, and MAP3K5 might serve as potential biomarkers and drug targets for GIONFH.
| S-EPMC9962586 | biostudies-literature
Project description:The purpose of this study was to investigate the preventive effect of ethyl 3,4-dihydroxybenzoate(EDHB) on steroid-associated femoral head osteonecrosis(ONFH) in a rabbit model. New Zealand white rabbits were randomly divided into two groups (prevention group and model group), each containing 24 rabbits. Osteonecrosis was induced by lipopolysaccharide(LPS) combined with methylprednisolone(MPS). The prevention group received an intraperitoneal injection of EDHB at 50 mg/kg body weight every other day starting three days before establishing rabbit models of osteonecrosis, for a total of nine doses. Osteonecrosis was verified by haematoxylin-eosin (HE) staining. The expression of HIF-1α and VEGF was analyzed by immunohistochemistry. Angiogenesis, apoptosis and microstructural parameters were also analyzed. The rabbit models of osteonecrosis were successfully established and observed by HE staining. Histopathological observations indicated that EDHB reduced the rate of empty lacunae and the incidence of osteonecrosis. Immunohistochemical staining for HIF-1α and VEGF suggested that EDHB therapy inhibited degradation of HIF-1α and promoted expression of VEGF. Ink artery infusion angiography and microvessel density analysis revealed that there were more microvessels in the prevention group than in the model group. The TUNEL apoptosis assay suggested that EDHB intervention could reduce the number of apoptotic cells in avascular osteonecrosis of the femoral head. Micro-CT scanning indicated that the treatment group had better microstructural parameters than the model group. EDHB prevents steroid-associated osteonecrosis of the femoral head in rabbits by promoting angiogenesis and inhibiting apoptosis of bone cells and hematopoietic tissue.
| S-EPMC4171501 | biostudies-literature
Project description:Steroid-induced osteonecrosis of femoral head (SONFH) is one of the most common bone disorders in humans. Statin treatment is beneficial in preventing the development of SONFH through anti-inflammation effects and inhibition of the glucocorticoid receptor (GR). However, potential mechanisms of statin action remain to be determined. In this study, pulse methylprednisolone (MP) treatment was used to induce SONFH in broilers, and then MP-treated birds were administrated with simvastatin simultaneously to investigate the changes in cartilage homeostasis. Meanwhile, chondrocytes were isolated, cultured, and treated with MP, simvastatin, or GR inhibitor in vitro. The changes in serum homeostasis factors, cell viability, and expression of GR were analyzed. The results showed that the morbidity of SONFH in the MP-treated group increased significantly compared with the simvastatin-treated and control group. Furthermore, MP treatment induced apoptosis and high-level catabolism and low-level anabolism in vitro and vivo, while simvastatin significantly decreased catabolism and slightly recovered anabolism via inhibiting GR and the hypoxia-inducible factor (HIF) pathway. The GR inhibitor or its siRNA mainly affected the catabolism of cartilage homeostasis in vitro. In conclusion, the occurrence of SONFH in broilers was related to the activation of GR and HIF pathway, and imbalance of cartilage homeostasis. Simvastatin and GR inhibitor maintained cartilage homeostasis via GR and the HIF pathway.
| S-EPMC9777187 | biostudies-literature