Articular Fibrocartilage-Targeted Therapy by Microtubule Stabilization
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE207148 | GEO | 2022/11/23
REPOSITORIES: GEO
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Project description:The fibrocartilage presented on the joint surface was caused by cartilage injury or degeneration. There is still a lack of effective strategies for fibrocartilage. Here, we hypothesized that the fibrocartilage could be viewed as a raw material for the renewal of hyaline cartilage and proposed a previously unidentified strategy of cartilage regeneration, namely, "fibrocartilage hyalinization." Cytoskeleton remodeling plays a vital role in modifying the cellular phenotype. We identified that microtubule stabilization by docetaxel repressed cartilage fibrosis and increased the hyaline cartilage extracellular matrix. We further designed a fibrocartilage-targeted negatively charged thermosensitive hydrogel for the sustained delivery of docetaxel, which promoted fibrocartilage hyalinization in the cartilage defect model. Moreover, the mechanism of fibrocartilage hyalinization by microtubule stabilization was verified as the inhibition of Sparc (secreted protein acidic and rich in cysteine). Together, our study suggested that articular fibrocartilage-targeted therapy in situ was a promising strategy for hyaline cartilage repair.
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Project description:Articular Fibrocartilage-Targeted Therapy by Microtubule Stabilization
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Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin.
2016-04-14 | GSE69447 | GEO
Project description:Connective tissue growthfactor (CTGF/CCN2) is a matricellular protein induced by transforming growth factor-beta (TGF-beta) and intimately involved with tissue repair and overexpressed in various fibrotic conditions. We have previously shown that keratinocytes in vitro downregulate TGF-beta induced expression of CTGF in fibroblasts by an interleukin-1 alfa (IL-1alfa) dependent mechanism. With this study we want to get a better overall perspective who fibroblasts respond on TGF-beta and in a TGF-Beta stinulated system, what effect addition of IL-1 alfa have. This to understand the expression of CTGF in human fibroblasts which in turn have implications for the pathogenesis of fibrotic conditions involving the skin. Microarray was performed on human skin fibroblast RNA from one patient, Fibroblasts were seeded in vitro as a control (Control, C), TGF-beta were added to fibroblasts and incubated for 16 h (addition of TGF-beta, T) and both IL-1alfa and TGF-beta were added to fibroblasts for 16 h (addition of IL-1alfa and TGF-beta, IT). Each condition (C,T and IT) were done in three replicates.
2016-04-14 | E-GEOD-69447 | biostudies-arrayexpress
Project description:The effects of spaceflight on cartilaginous structure are largely unknown. To address this deficiency, articular cartilage (AC) and sternal cartilage (SC) from mice exposed to 30 days of microgravity on the BION-M1 craft were investigated for pathological changes. The flight AC showed some evidence of degradation at the tissue level with loss of proteoglycan staining and a reduction in mRNA expression of mechano-responsive and structural cartilage matrix proteins compared to non-flight controls. These data suggest that degradative changes are underway in the AC extracellular matrix exposed to microgravity. In contrast, there was no evidence of cartilage breakdown in SC flight samples and the gene expression profile was distinct from that of AC with a reduction in metalloproteinase gene transcription. Since the two cartilages respond differently to microgravity we propose that each is tuned to the biomechanical environments in which they are normally maintained. That is, the differences between magnitude of normal terrestrial loading and the unloading of microgravity dictates the tissue response. Weight-bearing articular cartilage, but not minimally loaded sternal fibrocartilage, is negatively affected by the unloading of microgravity. We speculate that the maintenance of physiological loading on AC during spaceflight will minimize AC damage.
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Project description:Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of TGFβ1 as the major player in the pathogenesis of the disease. This study designed novel human- and mouse-specific siRNAs and siRNA/DNA chimeras targeting both human and mouse common sequences and evaluated their inhibitory activity in pulmonary fibrosis induced by bleomycin and lung-specific transgenic expression of human TGFβ1. Selective novel sequences of siRNA and siRNA/DNA chimeras efficiently inhibited pulmonary fibrosis, indicating their applicability as tools for treating fibrotic disease in humans. Total RNA was extracted from lung tissue from mice with bleomycin (BLM)-induced lung fibrosis treated with mouse TGFβ1 siRNAs or vehicle on different days after BLM infusion.
2011-11-22 | E-GEOD-28122 | biostudies-arrayexpress
Project description:Fibrosis is a common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor, but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging–genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.
2017-12-11 | GSE107909 | GEO
Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Here, we reveal a novel cistromic circuit in HSCs comprising the vitamin D receptor (VDR) and SMAD transcription factors that restrains the intensity of hepatic fibrogenesis. Ligand-activated VDR suppresses TGFβ1-induced pro-fibrotic gene expression in HSCs. Administration of a vitamin D analogue, calcipotriol, diminishes the fibrotic response in a mouse model of liver fibrosis, while VDR knockout mice spontaneous develop extensive hepatic fibrosis by age 6 months. Using ChIP-Seq, we find that the anti-fibrotic properties of VDR are due to crosstalk with SMAD, mediated by their co-occupancy of DNA-binding sites on pro-fibrotic genes. Specifically, SMAD binding potentiates local chromatin accessibility to enhance VDR recruitment at the same cis-regulatory elements, which reciprocally antagonizes the interaction between SMAD3 and chromatin and limits the assembly of transcriptional activation complexes at fibrotic genes, a process that is enhanced by the presence of VDR agonists. These results not only establish this coordinated VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis, but also support VDR as a potential drug target to ameliorate liver fibrosis. Identification of VDR, SMAD3 and H3 binding sites in human stellate LX2 cells that were pre-treated with calcipotriol (100nM) for 16 hrs (where calcipotriol treatment is indicated) followed by incubation of calcipotriol (100nM) or TGFβ1 (1ng/ml) for another 4 hours (where indicated).
2013-04-29 | E-GEOD-38103 | biostudies-arrayexpress
Project description:Background. Accumulation of extracellular matrix in the myocardium attenuates cardiac contractile function, and predisposes to arrhythmias and sudden cardiac death. Connective tissue growth factor (CTGF) is a matricellular protein that has been shown to promote development of cardiac fibrosis. Objectives. To investigate for the potential of CTGF monoclonal antibody (CTGF mAb) in protecting from development of cardiac fibrosis following myocardial infarction (MI), and to evaluate its effect during infarct repair and acute cardiac ischemia-reperfusion (I/R) injury. Methods. Mice were subjected to MI or to I/R injury and treated with either control IgG or CTGF mAb. Cultured human cardiac fibroblasts were used to investigate the signalling mechanisms modulated by CTGF mAb. Results. Treatment with CTGF mAb for four days from day three after MI improved survival, attenuated infarct expansion, and resulted in better preserved left ventricular (LV) systolic function. CTGF mAb therapy for six weeks from day seven after MI reduced the MI-induced increase in cardiomyocyte size, heart weight to body weight ratio and remote LV fibrosis. RNA sequencing analysis of LV samples showed that CTGF mAb induced expression of cardiac repair/developmental genes and normalized the MI-induced increase in expression of inflammatory/profibrotic genes. CTGF mAb induced c-Jun N-terminal kinase (JNK) phosphorylation in vivo and in vitro, and inhibition of JNK abrogated the reduced collagen production in CTGF mAb treated fibroblasts. Conclusions. Treatment with CTGF mAb induces expression of cardiac repair/developmental genes and inhibits expression of inflammatory/pro-fibrotic genes in MI hearts providing benefit during post-MI cardiac repair and reducing post-MI cardiac fibrosis.
2019-04-02 | GSE129134 | GEO
Project description:Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.
2024-10-06 | E-MTAB-14494 | biostudies-arrayexpress