The hypertrophy of the ligamentum flavum is assosciated with activation of the unfolded protein respone
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE113212 | GEO | 2018/04/17
REPOSITORIES: GEO
Similar Datasets
Project description:The hypertrophy of the ligamentum flavum is assosciated with activation of the unfolded protein respone
| PRJNA450431 | ENA
Project description:Lumbar spinal canal stenosis (LSCS) is one of the most common spinal disorders in elderly people, with the number of LSCS patients increasing due to the aging of the population. The ligamentum flavum (LF) is a spinal ligament located in the interior of the vertebral canal, and hypertrophy of the LF, which causes the direct compression of the nerve roots and/or cauda equine, is a major cause of LSCS. Although there have been previous studies on LF hypertrophy, its pathomechanism remains unclear. The purpose of this study is to establish a relevant mouse model of LF hypertrophy and to examine disease-related factors. First, we focused on mechanical stress and developed a loading device for applying consecutive mechanical flexion-extension stress to the mouse LF. After 12 weeks of mechanical stress loading, we found that the LF thickness in the stress group was significantly increased in comparison to the control group. In addition, there were significant increases in the area of collagen fibers, the number of LF cells, and the gene expression of several fibrosis-related factors. However, in this mecnanical stress model, there was no macrophage infiltration, angiogenesis, or increase in the expression of transforming growth factor-β1 (TGF-β1), which are characteristic features of LF hypertrophy in LSCS patients. We therefore examined the influence of infiltrating macrophages on LF hypertrophy. After inducing macrophage infiltration by micro-injury to the mouse LF, we found excessive collagen synthesis in the injured site with the increased TGF-β1 expression at 2 weeks after injury, and further confirmed LF hypertrophy at 6 weeks after injury. Our findings demonstrate that mechanical stress is a causative factor for LF hypertrophy and strongly suggest the importance of macrophage infiltration in the progression of LF hypertrophy via the stimulation of collagen production.
| S-EPMC5217959 | biostudies-literature
Project description:We isolated highly purified CD8+CD28+ and CD8+CD28- T cell populations from healthy young and elderly persons for gene expression profiling using Affymetrix oligonucleotide microarrays. We demonstrate that the gene expression profile of CD8+CD28- T cells is very similar in young and elderly persons. In contrast, CD8+CD28+ in elderly differ from CD8+CD28+ in young persons. Hierarchical clustering revealed that CD8+CD28+ in elderly are located between CD8+CD28+ in young and CD8?CD28- (young and old) T cells regarding their differentiation state. Our study demonstrates a dichotomy of gene expression levels between CD8+CD28+ T cells in young and elderly persons but a similarity between CD8+CD28- T cells in young and elderly persons. As CD8+CD28+ T cells from elderly and young persons are distinct due to a different composition of the population, these results suggest that the gene expression profile does not depend on chronological age but depends on the differentiation state of the individual cell types.
2010-09-03 | E-MEXP-2345 | biostudies-arrayexpress
Project description:Ligamentum flavum hypertrophy (LFH) is the most important component of lumbar spinal canal stenosis. Although the pathophysiology of LFH has been extensively studied, no method has been proposed to prevent or treat it. Since the transforming growth factor-? (TGF-?) pathway is known to be critical in LFH pathology, we investigated whether LFH could be prevented by blocking or modulating the TGF-? mechanism. Human LF cells were used for the experiments. First, we created TGF-? receptor 1 (TGFBR1) knock out (KO) cells with CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 biotechnology and treated them with TGF-?1 to determine the effects of blocking the TGF-? pathway. Subsequently, we studied the effect of CCN5, which has recently been proposed to modulate the TGF-? pathway. To assess the predisposition toward fibrosis, ?-smooth muscle actin (?SMA), fibronectin, collagen-1, collagen-3, and CCN2 were evaluated with quantitative real-time polymerase chain reaction, western blotting, and immunocytochemistry. The TGFBR1 KO LF cells were successfully constructed with high KO efficiency. In wild-type (WT) cells, treatment with TGF-?1 resulted in the overexpression of the messenger RNA (mRNA) of fibrosis-related factors. However, in KO cells, the responses to TGF-?1 stimulation were significantly lower. In addition, CCN5 and TGF-?1 co-treatment caused a notable reduction in mRNA expression levels compared with TGF-?1 stimulation only. The ?SMA protein expression increased with TGF-?1 but decreased with CCN5 treatment. TGF-?1 induced LF cell transdifferentiation from fibroblasts to myofibroblasts. However, this cell transition dramatically decreased in the presence of CCN5. In conclusion, CCN5 could prevent LFH by modulating the TGF-? pathway. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2634-2644, 2019.
| S-EPMC6899892 | biostudies-literature
Project description:Hypertrophy of the ligamentum flavum (HLF) is one of the common causes of lumbar spinal stenosis (LSS). The key molecules and mechanisms responsible for HLF remain unclear. Here, we used an integrated transcriptome and proteomics analysis of human ligamentum flavum (LF), and subsequent immunohistochemistry and real-time PCR assays, to show upregulation of CRLF1 to be the dominant response to HLF. TGF-β1 significantly increased mRNA expression of CRLF1 through SMAD3 pathway. CRLF1 enhanced LF fibrosis via ERK signaling pathway at the post-transcriptional level and was required for the pro-fibrotic effect of TGF-β1. Knockdown of CRLF1 was shown here to reduce fibrosis caused by inflammatory cytokines and mechanical stress. Furthermore, we found that bipedal standing posture can cause HLF and upregulation of CRLF1 expression in mice LF. Overexpression of CRLF1 was indicated to cause HLF in vivo, whereas CRLF1 knockdown impeded the formation of HLF in bipedal standing mice. These results revealed a crucial role of CRLF1 in LF hypertrophy. We propose that inhibition of CRLF1 is a potential therapeutic strategy to treat HLF.
| S-EPMC7533558 | biostudies-literature
Project description:To further investigate the role of hyaluronan and the regulation of its synthesis in cardiac hypertrophy, quantitative measurements of myocardial hyaluronan was correlated to gene transcription in hypertrophic cardiac tissue. Factor analysis was used to study correlation over time.
2010-05-01 | GSE21600 | GEO
Project description:Pathological growth of cardiomyocytes during hypertrophy is characterized by excess protein synthesis; however, the regulatory mechanism remains largely unknown. Using a neonatal rat ventricular myocyte (NRVMs) model, here we find that the expression of nucleosome assembly protein 1 like 5 (Nap1l5) is upregulated in phenylephrine (PE)-induced hypertrophy. Knockdown of Nap1l5 expression by siRNA significantly blocks cell size enlargement and pathological gene induction after PE treatment. In contrast, Adenovirus-mediated Nap1l5 overexpression significantly aggravates the pro-hypertrophic effects of PE on NRVMs. RNA-seq analysis reveals that Nap1l5 knockdown reverses the pro-hypertrophic transcriptome reprogramming after PE treatment. Whereas immune response is dominantly enriched in the upregulated genes, oxidative phosphorylation, cardiac muscle contraction and ribosome related pathways are remarkably enriched in the down-regulated genes. Although PRC2 and PRC1 are involved in Nap1l5-mediated gene regulation, Nap1l5 does not directly alter the levels of global histone methylations. However, puromycin incorporation assay shows that Nap1l5 is both necessary and sufficient to drive the increased protein synthesis rate in cardiomyocyte hypertrophy. This is attributable to a direct regulation of ribosome assembly by Nap1l5. Our findings demonstrate a previously unrecognized role of Nap1l5 in translation control during cardiac hypertrophy.
2022-10-09 | GSE185699 | GEO
Project description:We set out to determine the role of the IRE1/XBP1 pathway, the most ancient and highly conserved endoplasmic reticulum (ER) stress-sensing pathway of the unfolded protein response (UPR), in Schmid metaphyseal chondrodysplasia (MCDS). RNA derived from hypertrophic zones microdissected from growth plates of wildtype mice, mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), mice carrying a COL10A1 pN617K mutation (ColXN617K), and compound mutants (C/X) was analyzed by whole genome microarray analysis. 1633 probes were differentially expressed between ColXN617K and wildtype, 215 probes were differentially expressed between Xbp1Cart?Ex2 and wildtype, and 1337 probes were differentially expressed between C/X and wildtype. 885 probes were differentially expressed between ColXN617K and wildtype but not Xbp1Cart?Ex2 and wildtype or C/X and wildtype, thus representing the XBP1-dependent response to hypertrophic chondrocyte ER stress. 688 probes were differentially expressed between ColXN617K and wildtype and between C/X and wildtype but not Xbp1Cart?Ex2 and wildtype, thus representing the XBP1-independent response to hypertrophic chondrocyte ER stress. Results were validated by qPCR. Entire growth plate hypertrophic zones were microdissected from one tibia from each of three 2-week old wildtype mice, three 2-week old mice carrying a COL10A1 p.N617K mutation (ColXN617K), three 2-week old mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), and three 2-week old mice resulting from a cross between ColXN617K and Xbp1Cart?Ex2 (C/X).
2015-08-21 | E-GEOD-72261 | biostudies-arrayexpress
Project description:Pathological cardiac hypertrophy is driven by neurohormonal activation of specific G protein-coupled receptors (GPCRs) in cardiomyocytes and is accompanied by large-scale changes in cardiomyocyte gene expression. These transcriptional changes require activity of positive transcription elongation factor b (P-TEFb), which is recruited to target genes by the bromodomain protein Brd4 or the Super Elongation Complex (SEC). Here we describe GPCR-specific regulation of these P-TEFb complexes and a novel mechanism for activating Brd4 in primary neonatal rat cardiomyocytes. The SEC was required for the hypertrophic response downstream of either the α1-adrenergic receptor (α1-AR) or the endothelin receptor (ETR). In contrast, Brd4 inhibition selectively impaired the α1-AR response. This was corroborated by the finding that activation of α1-AR, but not ETR, increased Brd4 occupancy at promoters and super enhancers of hypertrophic genes. Transcriptome analysis demonstrated that activation of both receptors initiated similar gene expression programs, but that Brd4 inhibition attenuated hypertrophic genes more robustly following α1-AR activation. Finally, we show that protein kinase A (PKA) is required for α1-AR stimulation of Brd4 chromatin occupancy. The differential role of the Brd4/P-TEFb complex in response to distinct GPCR pathways has potential clinical implications as therapies targeting this complex are currently being explored for heart failure.
2020-05-22 | GSE147402 | GEO
Project description:Degenerative spinal stenosis is a chronic disease that affects the spinal ligaments and associated bones, resulting in back pain and disorders of the limbs among the elderly population. There are few preventive strategies for such ligament degeneration. We here aimed to establish a comprehensive transcriptomic atlas of ligament tissues to identify high-priority targets for pharmaceutical treatment of ligament degeneration. Here, single-cell RNA sequencing was performed on six degenerative ligaments and three traumatic ligaments to understand tissue heterogeneity.
2024-07-31 | GSE271018 | GEO