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Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits.

ABSTRACT: PURPOSE:Lovastatin is an important medicine and it shows a significant effect against glucocorticoid-induced necrosis of the femoral head. This study aimed to investigate the effect of lovastatin on preventing necrosis of the femoral head of by serum metabolomics strategy. METHODS:Adult healthy adult Japanese white rabbits were divided into three groups: control group, model group, and drug group. The pathologic changes of femoral head were assessed with magnetic resonance imaging and microscope. Metabolomics based on ultra-high performance liquid chromatography tandem mass spectrometry analysis was used to analyze the collected serum sample. Data were analyzed using principal component analysis, partial least squares-discriminate analysis, and orthogonal partial least squares-discriminant analysis. All potential metabolites were identified by comparing with human metabolome database, Metlin database, lipid maps, and chemspider database. RESULTS:Eleven potential biomarkers were noted and identified as potential biomarkers. The change of biomarkers suggested that lovastatin on preventing necrosis of the femoral head may affect glycerophospholipid metabolism, linoleic acid metabolism, sphingolipid metabolism, alpha-linolenic acid metabolism, pyrimidine metabolism, and arachidonic acid metabolism. CONCLUSION:The study suggested that lovastatin could prevent the glucocorticoid-induced necrosis of the femoral head of rabbits. The possible reasons were closely associated with adjusting the lipid metabolism, inhibiting adipogenesis, and delaying the osteocyte apoptosis.

SUBMITTER: Ren X

PROVIDER: S-EPMC7594276 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits.

Ren Xiangnan X Shao Zixing Z Fan Wu W Wang Zixuan Z Chen Kaiyun K Yu Xuefeng X

Journal of orthopaedic surgery and research 20201028 1

<h4>Purpose</h4>Lovastatin is an important medicine and it shows a significant effect against glucocorticoid-induced necrosis of the femoral head. This study aimed to investigate the effect of lovastatin on preventing necrosis of the femoral head of by serum metabolomics strategy.<h4>Methods</h4>Adult healthy adult Japanese white rabbits were divided into three groups: control group, model group, and drug group. The pathologic changes of femoral head were assessed with magnetic resonance imaging ...[more]

PMID: 33115522

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Project description:The steriod-induced necrosis of femoral head(SINFH) is a serious clinical problem and the underlying mechanism of this disease remains unknown. As its etiology and pathogenesis are not clear, there hasn’t been an effective treatment yet. In-depth studies on its pathogenesis will provide important information for the prevention and treatment of this devastated disease. Animal model researches are helpful to a better understanding of its etiology and pathogenesis, to early diagnosis and treatments and provide the basis for clinical treatment It has been proved that the occurrence of SINFH is related to gene itself and its polymorphism. These studies, in which only one or a few genes were investigated, could not provide a comprehensive understanding to the pathogenesis of SINFH. We used microarrays to compare the gene expression profile of SINFH rats with that of normal rats and identified gene expression changes between SINFH rats and normal rats. Adult healthy male Wistar rats(body weight 200±10g) were randomly divided into control and experimental groups. All the rats were given injection of E. coli endotoxin at a dose of 20μg/kg body weight into abdominal cavity for two times with a 24 hour interval. 24 hours after the second administration of E. coli endotoxin, methylprednisolone 40mg/kg was administered into the left gluteus muscle of experimental group rats for three times with a 24 hour interval. Rats were then killed 6 weeks after steroid administration. In experiment, immediately after death the left femoral heads were isolated. Femoral heads were used for RNA extraction and hybridization on Affymetrix microarrays. We sought to obtain the gene expression profile of SINFH rats and that of normal rats in order to identified gene expression changes between SINFH rats and normal rats by comparing the gene expression profile of SINFH rats with that of normal rats. To that end, we have established the gene expression profiles of normal and SINFH disease of rat femoral head and found out differentially expressed genes.

Project description:The prohibition of the use of growth-promoting drug additives in feeds was implemented in China in 2020. However, rabbits can experience symptoms of intestinal disease, such as diarrhea and flatulence, when switching from standard normal diets with antibiotics to antibiotic-free diets. The molecular mechanisms related to the occurrence of these diseases as well as associated physiological and metabolic changes in the intestine are unclear. Thus, the objectives of this study were to study the pathogenesis of intestinal inflammation using untargeted metabolomics. This was done to identify differential metabolites between a group of antibiotic-free feed Hyplus rabbits (Dia) whose diet was abruptly changed from a standard normal diet with antibiotics to an antibiotic-free diet, and an antibiotic diet group Hyplus rabbits (Con) that was fed a standard normal diet with antibiotics. Morphological damage to the three intestinal tissues was determined through visual microscopic examination of intestinal Dia and Con tissue samples stained with hematoxylin and eosin (HE). A total of 1969 different metabolites were identified in the three intestinal tissues from Dia and Con rabbits. The level of 1280 metabolites was significantly higher and the level of 761 metabolites was significantly lower in the Dia than in the Con group. These differential metabolites were involved in five metabolic pathways associated with intestinal inflammation (tryptophan metabolism, pyrimidine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, lysine degradation, and bile secretion). Rabbits in the Dia group developed metabolic disorders that affected the intestinal microbiota and changed the permeability of the intestinal tract, thereby triggering intestinal inflammation, affecting feed utilization, reducing production performance, and activating the intestinal tract self-repair mechanism. Thus, the abrupt transition from a diet with antibiotics to an antibiotic-free diet affected the structure and metabolism of the intestinal tract in Hyplus rabbits. Consequently, to avoid these problems, the antibiotic content in a rabbit diet should be changed gradually or alternative antibiotics should be found.

Project description:BackgroundThe etiology and pathology osteonecrosis of the femoral head (ONFH) are not completely clarified. As a cytokine participating in systemic inflammation, tumor necrosis factor alpha (TNFα) has been shown to be involved in the pathogenesis of ONFH. However, the role of TNFα in ONFH is not clearly clarified. In the present study, we investigated the effects of TNFα on proliferation, angiogenesis, and osteogenic differentiation of rat bone mesenchymal stem cells (rMSCs) and the underlying mechanisms.MethodsAll femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we evaluated TNFα content by ELISA and the relative expression levels of genes by quantitative real-time PCR and western blot. Also, immunohistochemistry staining was performed to observe the expression of Runx2 in the bone samples. Chick embryo chorioallantoic membrane (CAM) assay was performed to observe the effect of TNFα on angiogenesis. The genomic DNAs were treated by bisulfite modification, and methylation status of CpG sites in the CpG islands of human and rat Runx2 gene promoter was determined by DNA sequencing. The binding of H3K4me3 and H3K27me3 in Runx2 promoter was checked by ChIP assay. RNA-seq analysis was used to find out the genes and pathways changed by TNFα in rMSCs.ResultsThe results demonstrate TNFα promotes cell proliferation and angiogenesis whereas inhibits osteogenesis. Epigenetic regulations including DNA methylation and histone modifications play important roles in mediating the effect of TNFα on osteogenic differentiation. We find an increased rate of CpG methylation in rat Runx2 promoter in TNFα-treated rMSCs, as well as significantly increased occupancy of H3K27me3 in Runx2 gene promoter. The content of TNFα in necrotic tissue is much lower than that of normal tissue. And relevantly, human Runx2 promoter is demethylated in necrotic tissue using bone samples from patient with ONFH. In addition, we have observed that Wnt signaling pathway is inhibited by TNFα as multiple Wnts are markedly decreased in TNFα-treated rMSCs by RNA-seq analysis.ConclusionTaken together, our study shows that TNFα plays complicated roles in the pathogenesis of ONFH, including proliferation, angiogenesis, and osteogenesis. Targeting TNFα should not be considered as an applicable strategy to inhibit the progression of ONFH.

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Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits.

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Untargeted metabolomics reveals the effect of lovastatin on steroid-induced necrosis of the femoral head in rabbits.

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