PTGS2 identified as a biomarker of glucocorticoid-induced osteonecrosis of the femoral head and an enhancer of osteogenesis.
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ABSTRACT:
SUBMITTER: Zhang Q
PROVIDER: S-EPMC10066245 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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PTGS2 identified as a biomarker of glucocorticoid-induced osteonecrosis of the femoral head and an enhancer of osteogenesis.
Zhang Qingyu Q Lu Shun S Zhou Dongsheng D Dong Jun J Liu Fanxiao F
Genes & diseases 20220316 1
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Project description:BackgroundGlucocorticoid-associated osteonecrosis of the femoral head (GA-ONFH) is a progressive bone disorder which frequently results in femoral head collapse and hip joint dysfunction. Sclerostin (SOST) is principally secreted by osteocytes in bone and plays an important role in bone homeostasis and homeostasis of skeletal integrity. Our previous study reported that short-term use of glucocorticoid increased serum sclerostin levels. Here this study is aimed to identify whether sclerostin played an essential role in the occurrence and development of GA-ONFH.MethodsGlucocorticoid-induced osteonecrosis of femoral head (ARCO stage II) samples were collected and sclerostin staining was conducted. Osteocyte cell line Ocy454, MC3T3-E1 and endothelial cells was used. MC3T3-E1 or endothelial cells were co-cultured with Ocy454 or SOST-silencing Ocy454 in presence of dexamethasone to mimic the crosstalk of various cells in the bone niche. GA-ONFH rat model and SOST knockout model was built to better understand the phenomenon in vivo.ResultsSclerostin was highly concentrated in osteonecrosis patient sample in the necrotic area. Co-culture with osteocytes aggravated the inhibition of dexamethasone on MC3T3-E1 and endothelial cells. Sclerostin derived from osteocytes impaired osteogenesis and angiogenesis via inhibiting the Wnt pathway. In GA-ONFH rat model, SOST knockout ameliorated the incidence of osteonecrosis and improved bone metabolism compared with the wild type group through histological, immunohistochemical and bone metabolic analyses.ConclusionSclerostin contribute to pathologic process of GA-ONFH by impairing osteogenesis and angiogenesis.
| S-EPMC11439244 | biostudies-literature
Project description:Subchondral bone samples from six patients who underwent primary total hip arthroplasty (three ONFH patients and three patients in control group with femoral neck fracture) were obtained.
2022-03-12 | E-MTAB-11493 | biostudies-arrayexpress
Project description:In glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH), downregulated osteogenic ability and damaged blood supply are two key pathogenic mechanisms. Studies suggested that cannabinoid receptor 2 (CB2) is expressed in bone tissue and it plays a positive role in osteogenesis. However, whether CB2 could enhance bone formation and blood supply in GC-induced ONFH remains unknown. In this study, we focused on the effect of CB2 in GC-induced ONFH and possible mechanisms in vitro and in vivo. By using GC-induced ONFH rat model, rat-bone mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) to address the interaction of CB2 in vitro and in vivo, we evaluate the osteogenic and angiogenic effect variation and possible mechanisms. Micro-CT, histological staining, angiography, calcein labeling, Alizarin red staining (ARS), alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) staining, TUNEL staining, migration assay, scratch assay, and tube formation were applied in this study. Our results showed that selective activation of CB2 alleviates GC-induced ONFH. The activation of CB2 strengthened the osteogenic activity of BMSCs under the influence of GCs by promotion of GSK-3β/β-catenin signaling pathway. Furthermore, CB2 promoted HUVECs migration and tube-forming capacities. Our findings indicated that CB2 may serve as a rational new treatment strategy against GC-induced ONFH by osteogenesis activation and maintenance of blood supply.
| S-EPMC8556843 | biostudies-literature
Project description:Background: The lack of effective biomarkers makes it difficult to achieve early diagnosis and intervention for osteonecrosis of the femoral head (ONFH). Hence, we aimed to identify novel long noncoding RNA (lncRNA) biomarkers for ONFH. Methods: High-throughput RNA sequencing was performed to detect lncRNA and mRNA expression levels in subchondral bone samples from three patients with ONFH and three patients with femoral neck fractures. Integrated bioinformatics analyses were conducted to identify lncRNAs associated with ONFH development and their potential functions and signaling pathways. A co-expression network was constructed based on the gene time-series expression data in GSE113253. After selecting lncRNA GAS5 as a novel biomarker for ONFH, bone marrow mesenchymal stem cell (BMSC) osteogenic differentiation assays were performed to verify the association between lncRNA GAS5 and osteogenic differentiation. Alkaline phosphatase (ALP) staining and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were used to measure the osteogenic phenotype and lncRNA GAS5 expression. Finally, for further validation, ONFH rat models were established, and lncRNA GAS5 expression in subchondral bone was detected by RT-qPCR. Results: We identified 126 and 959 differentially expressed lncRNAs and genes, respectively. lncRNA GAS5 expression level was significantly downregulated in patients with ONFH compared to the control group patients. The BMSC osteogenic differentiation assays showed that ALP activity increased gradually from days 3 to 7, while the lncRNA GAS5 expression level was significantly upregulated in the osteogenic differentiation induction groups. Furthermore, in vivo experiments suggested that the bone volume/tissue volume value and trabecular thickness significantly decreased in the ONFH rat model group compared to the control group, whereas the trabecular space significantly increased in the ONFH group compared to the control group. In addition, the lncRNA GAS5 expression level significantly decreased in the ONFH rat model group. Conclusion: The lncRNA GAS5 expression level was highly associated with BMSC osteogenic differentiation and was significantly downregulated in both the subchondral trabecular bone tissue of ONFH patients and ONFH rat models. Therefore, lncRNA GAS5 can serve as an ONFH osteogenic biomarker to provide an effective target for early diagnosis and molecular therapy of ONFH.
| S-EPMC8980611 | 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: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:Vascular injury is considered an important pathological process during glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH). In this study, we tried to investigate whether the endoplasmic reticulum (ER) stress is triggered in the GC-induced endotheliocyte (EC) apoptosis and ONFH. The results showed that a GC upregulated the expression of ER stress-related proteins, and PERK-CHOP signaling played an important role and induced EC apoptosis. The inhibition of PERK by GSK2656157 significantly decreased the GC-induced EC apoptosis in vitro and in vivo, thus protecting a rat model from vascular injury and significantly preventing GC-induced ONFH.
| S-EPMC6990927 | 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: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