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Glucocorticoids Significantly Influence the Transcriptome of Bone Microvascular Endothelial Cells of Human Femoral Head.

ABSTRACT: Appropriate expression and regulation of the transcriptome, which mainly comprise of mRNAs and lncRNAs, are important for all biological and cellular processes including the physiological activities of bone microvascular endothelial cells (BMECs). Through an intricate intracellular signaling systems, the transcriptome regulates the pharmacological response of the cells. Although studies have elucidated the impact of glucocorticoids (GCs) cell-specific gene expression signatures, it remains necessary to comprehensively characterize the impact of lncRNAs to transcriptional changes.BMECs were divided into two groups. One was treated with GCs and the other left untreated as a paired control. Differential expression was analyzed with GeneSpring software V12.0 (Agilent, Santa Clara, CA, USA) and hierarchical clustering was conducted using Cluster 3.0 software. The Gene Ontology (GO) analysis was performed with Molecular Annotation System provided by CapitalBio Corporation.Our results highlight the involvement of genes implicated in development, differentiation and apoptosis following GC stimulation. Elucidation of differential gene expression emphasizes the importance of regulatory gene networks induced by GCs. We identified 73 up-regulated and 166 down-regulated long noncoding RNAs, the expression of 107 of which significantly correlated with 172 mRNAs induced by hydrocortisone.Transcriptome analysis of BMECs from human samples was performed to identify specific gene networks induced by GCs. Our results identified complex RNA crosstalk underlying the pathogenesis of steroid-induced necrosis of femoral head.

SUBMITTER: Yu QS

PROVIDER: S-EPMC4717923 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Glucocorticoids Significantly Influence the Transcriptome of Bone Microvascular Endothelial Cells of Human Femoral Head.

Yu Qing-Sheng QS Guo Wan-Shou WS Cheng Li-Ming LM Lu Yu-Feng YF Shen Jian-Ying JY Li Ping P

Chinese medical journal 20150701 14

<h4>Background</h4>Appropriate expression and regulation of the transcriptome, which mainly comprise of mRNAs and lncRNAs, are important for all biological and cellular processes including the physiological activities of bone microvascular endothelial cells (BMECs). Through an intricate intracellular signaling systems, the transcriptome regulates the pharmacological response of the cells. Although studies have elucidated the impact of glucocorticoids (GCs) cell-specific gene expression signature ...[more]

PMID: 26168838

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Project description:ObjectivesBone microvascular endothelial cells (BMECs) played an important role in the pathogenesis of glucocorticoid-induced osteonecrosis of femoral head (GCS-ONFH), and exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) may provide an effective treatment. This study aimed to evaluate the effects of BMSC-Exos and internal microRNA-210-3p (miRNA-210) on GCS-ONFH in an in vitro hydrocortisone-induced BMECs injury model and an in vivo rat GCS-ONFH model.MethodsBMECs, BMSCs and BMSC-Exos were isolated and validated. BMECs after the treatment of hydrocortisone were cocultured with different concentrations of BMSC-Exos, then proliferation, migration, apoptosis and angiogenesis of BMECs were evaluated by CCK-8, Annexin V-FITC/PI, cell scratch and tube formation assays. BMSCs were transfected with miRNA-210 mimics and miRNA-210 inhibitors, then BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor secreted from such cells were collected. The differences between BMSC-Exos, BMSC-ExosmiRNA-210 mimic and BMSC-ExosmiRNA-210 inhibitor in protecting BMECs against GCS treatment were analyzed by methods mentioned above. Intramuscular injections of methylprednisolone were performed on Sprague-Dawley rats to establish an animal model of GCS-ONFH, then tail intravenous injections of BMSC-Exos, BMSC-ExosmiRNA-210 mimic or BMSC-ExosmiRNA-210 inhibitor were conducted after methylprednisolone injection. Histological and immunofluorescence staining and micro-CT were performed to evaluate the effects of BMSC-Exos and internal miRNA-210 on the in vivo GCS-ONFH model.ResultsDifferent concentrations of BMSC-Exos, especially high concentration of BMSC-Exos, could enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs treated with GCS. Compared with BMSC-Exos, BMSC-ExosmiRNA-210 mimic could further enhance the proliferation, migration and angiogenesis ability and reduce the apoptosis rates of BMECs, while BMECs in the GCS + BMSC-ExosmiRNA-210 inhibitor group showed reduced proliferation, migration and angiogenesis ability and higher apoptosis rates. In the rat GCS-ONFH model, BMSC-Exos, especially BMSC-ExosmiRNA-210 mimic, could increase microvascular density and enhance bone remodeling of femoral heads.ConclusionsBMSC-Exos containing miRNA-210 could serve as potential therapeutics for protecting BMECs and ameliorating the progression of GCS-ONFH.

Project description:BackgroundSteroid-induced osteonecrosis of the femoral head (SONFH) is a disorder that causes severe disability in patients and has a high incidence worldwide. Although glucocorticoid (GC)-induced apoptosis of osteoblasts is an important cytological basis of SONFH, the detailed mechanism underlying SONFH pathogenesis remains elusive. PI3K/AKT signaling pathway was reported to involve in cell survival and apoptosis.ObjectiveWe explored the role of PI3K/AKT/FOXO1 signaling pathway and its downstream targets during glucocorticoid -induced osteonecrosis of the femoral head.MethodsWe obtained gene expression profile of osteoblasts subjected to dexamethasone (Dex) treatment from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened out and functional enrichment analysis were conducted by bioinformatics analysis. In vitro, we analyzed Dex-induced apoptosis in MC3T3-E1 cells and explored the role of PI3K/AKT/FOXO1 signaling pathway in this phenomenon by employing siRNA-FOXO1 and IGF-1(PI3K/AKT agonist). Finally, we verified our results in a rat model of SONFH.ResultsIn Dex-treated osteoblasts, DEGs were mainly enriched in the FOXO signaling pathway. Dex inhibited MC3T3-E1 cell viability in a dose-dependent effect and induced apoptosis by increasing the expression levels of FOXO1, Bax, cleaved-Caspase-3, and cleaved-Caspase-9, while reducing the expression of Bcl-2. Notably, these results were reversed by siRNA-FOXO1 treatment. Dex inhibited PI3K/AKT signaling pathway, upregulated FOXO1 expression and increased FOXO1 nuclear translocation, which were reversed by IGF-1. Compared to normal rats, the femoral head of SONFH showed increased expression of FOXO1, increased number of apoptotic cells, and empty osteocytic lacunas, as well as decreased bone tissue content and femoral head integrity. Significantly, the effects of GC-induced SONFH were alleviated following IGF-1 treatment.ConclusionDex induces osteoblast apoptosis via the PI3K/AKT/FOXO1 signaling pathway. Our research offers new insights into the underlying molecular mechanisms of glucocorticoid-induced osteonecrosis in SONFH and proposes FOXO1 as a therapeutic target for this disease.

Project description:Teriparatide (TPTD) reduces risk of both vertebral and nonvertebral fracture, but increases bone mineral density (BMD) much more at the spine than the hip. TPTD and mechanical loading may have a synergistic anabolic effect on BMD, which may help explain these site-specific differences. Under normal daily activity, the femoral neck (FN) is under bending, placing one side under tension and the other under compression. We sought to further understand the relationship between mechanical loading and TPTD at the hip by investigating the effect of tensile versus compressive loading on TPTD stimulated bone formation indices in the human FN. Thirty-eight patients receiving total hip replacements for osteoarthritis were randomized to receive placebo (PBO) or TPTD for a mean treatment duration of 6 weeks prior to surgery, and double tetracycline labeling was administered to allow assessment of bone formation. The FN was harvested during surgery and analyzed for dynamic bone formation indices in the compressive and tensile regions of the endocortical and periosteal envelopes. Regression models relating outcome measures to patient characteristics including sex, age, body weight, and FN geometry were also analyzed. Overall, bone formation was higher with TPTD versus placebo on the endocortical surface, but not the periosteal surface. The level of bone formation in both TPTD and placebo groups was greater on the tensile endocortical surface and the compressive periosteal surface. There was a trend toward decreased endocortical eroded surface with TPTD in the compressive but not the tensile region. Patient age and sex explained the greatest variability in endocortical bone formation, and patient body mass and sex explained the greatest variability in periosteal bone formation. Our data represent the first dynamic comparison of teriparatide treatment under two loading modalities in human FN samples. Future work could determine whether specific hip loading intervention could amplify the benefits of teriparatide on the hip in clinical settings.

Dataset Information

Glucocorticoids Significantly Influence the Transcriptome of Bone Microvascular Endothelial Cells of Human Femoral Head.

Publications

Glucocorticoids Significantly Influence the Transcriptome of Bone Microvascular Endothelial Cells of Human Femoral Head.

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