Dataset Information

High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing.

ABSTRACT: Diabetes interferes with fracture repair; therefore, we investigated mechanisms of impaired fracture healing in a model of multiple low-dose streptozotocin-induced diabetes. Microarray and gene set enrichment analysis revealed an up-regulation of gene sets related to inflammation, including tumor necrosis factor (TNF) signaling in the diabetic group, when cartilage is being replaced by bone on day 16, but not on days 12 or 22. This change coincided with elevated osteoclast numbers and accelerated removal of cartilage in the diabetic group (P < 0.05), which was reflected by smaller callus size. When diabetic mice were treated with the TNF-specific inhibitor, pegsunercept, the number of osteoclasts, cartilage loss, and number of TNF-alpha and receptor activator for nuclear factor kB ligand positive chondrocytes were significantly reduced (P < 0.05). The transcription factor forkhead box 01 (FOXO1) was tested for mediating TNF stimulation of osteoclastogenic and inflammatory factors in bone morphogenetic protein 2 pretreated ATDC5 and C3H10T1/2 chondrogenic cells. FOXO1 knockdown by small-interfering RNA significantly reduced TNF-alpha, receptor activator for nuclear factor kB ligand, macrophage colony-stimulating factor, interleukin-1alpha, and interleukin-6 mRNA compared with scrambled small-interfering RNA. An association between FOXO1 and the TNF-alpha promoter was demonstrated by chromatin immunoprecipitation assay. Moreover, diabetes increased FOXO1 nuclear translocation in chondrocytes in vivo and increased FOXO1 DNA binding activity in diabetic fracture calluses (P < 0.05). These results suggest that diabetes-enhanced TNF-alpha increases the expression of resorptive factors in chondrocytes through a process that involves activation of FOXO1 and that TNF-alpha dysregulation leads to enhanced osteoclast formation and accelerated loss of cartilage.

SUBMITTER: Alblowi J

PROVIDER: S-EPMC2751554 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing.

Alblowi Jazia J Kayal Rayyan A RA Siqueira Michelle M McKenzie Erin E Krothapalli Nanarao N McLean Jody J Conn Jason J Nikolajczyk Barbara B Einhorn Thomas A TA Gerstenfeld Louis L Graves Dana T DT

The American journal of pathology 20090910 4

Diabetes interferes with fracture repair; therefore, we investigated mechanisms of impaired fracture healing in a model of multiple low-dose streptozotocin-induced diabetes. Microarray and gene set enrichment analysis revealed an up-regulation of gene sets related to inflammation, including tumor necrosis factor (TNF) signaling in the diabetic group, when cartilage is being replaced by bone on day 16, but not on days 12 or 22. This change coincided with elevated osteoclast numbers and accelerate ...[more]

PMID: 19745063

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Project description:It is commonly observed that patients with bone fracture concomitated with traumatic brain injury (TBI) had significantly increased fracture healing while the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) were known for paly complicated roles in bone homeostasis while its role in TBI accelerated fracture were rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatical analysis. Blood samples from 3 fracture only patients, 3 fracture concomitated with TIB patients and 3 healthy controls were harvested and were subsequently subjected to transcriptome lncRNAs sequencing. Differentially expression genes were identified, and pathway enrichment were performed by Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyze. High high-dimensional data portraying by self-organizing map (SOM) machine learning was applied to further interpret the data. A xCell method were then used to predict cellular behavior in all samples based on gene expression profiles and a lncRNA-cell interaction network were generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on traumatic brain injury related- and damage repair related-pathways. SOM analyzes revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly down-regulated while microvascular endothelia cells were predicated significantly up-regulated with TBI/Fr group was the lowest or highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expression lcnRNA that related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells and endothelia cells.

Project description:It is commonly observed that patients with bone fracture concomitant with traumatic brain injury (TBI) had significantly increased fracture healing, but the underlying mechanisms were not fully revealed. Long non-coding RNAs (lncRNAs) are known to play complicated roles in bone homeostasis, but their role in TBI accelerated fracture was rarely reported. The present study was designed to determine the role of lncRNAs in TBI accelerated fracture via transcriptome sequencing and further bioinformatics analyses. Blood samples from three fracture-only patients, three fracture concomitant with TBI patients, and three healthy controls were harvested and were subsequently subjected to transcriptome lncRNA sequencing. Differentially expressed genes were identified, and pathway enrichment was performed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. High-dimensional data visualization by self-organizing map (SOM) machine learning was applied to further interpret the data. An xCell method was then used to predict cellular behavior in all samples based on gene expression profiles, and an lncRNA-cell interaction network was generated. A total of 874 differentially expressed genes were identified, of which about 26% were lncRNAs. Those identified lncRNAs were mainly enriched on TBI-related and damage repair-related pathways. SOM analyses revealed that those differentially expressed lncRNAs could be divided into three major module implications and were mainly enriched on transcriptional regulation and immune-related signal pathways, which promote us to further explore cellular behaviors based on differentially expressed lncRNAs. We have predicted that basophils, CD8+ T effector memory cells, B cells, and naïve B cells were significantly downregulated, while microvascular endothelial cells were predicted to be significantly upregulated in the Fr/TBI group, was the lowest and highest, respectively. ENSG00000278905, ENSG00000240980, ENSG00000255670, and ENSG00000196634 were the most differentially expressed lncRNAs related to all changes of cellular behavior. The present study has revealed for the first time that several critical lncRNAs may participate in TBI accelerated fracture potentially via regulating cellular behaviors of basophils, cytotoxic T cells, B cells, and endothelial cells.

Dataset Information

High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing.

Publications

High levels of tumor necrosis factor-alpha contribute to accelerated loss of cartilage in diabetic fracture healing.

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