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Project description:<p>Mechanical force is critical for the development and remodeling of bone. Here we report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine (ADMA) via regulating the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 (Ddah1) expression in osteoblasts. The presence of -394 4N del/ins polymorphism of Ddah1 and higher serum ADMA concentration are negatively associated with bone mineral density. Global or osteoblast-specific deletion of Ddah1 leads to increased ADMA level but reduced bone formation. Further molecular study unveils that mechanical stimulation enhances TAZ/SMAD4-induced Ddah1 transcription. Deletion of Ddah1 in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. Taken together, the study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation.</p>
2021-11-23 | MTBLS3725 | MetaboLights
Project description:Mechanical force is a crucial external stimulus that plays a significant role in regulating bone structure and remodeling. Excessive loading of the bone and joint can lead to increased catabolism, chondrocyte necrosis, apoptosis and damage to the collagen network of bone(3–5). Osteoarthritis (OA), a degenerative osteoarticular disease, is associated with abnormal mechanical force stimulation, which can occur in various joints such as knee, temporomandibular joint [TMJ], shoulder and hip(6). Conversely, the absence of mechanical loading, such as prolonged bed rest or exposure to a microgravity environment in space, can result in a rapid decrease in bone mass and strength. Understanding how mechanical stimuli regulate bone homeostasis is crucial for exploring therapeutic strategies for bone metabolic diseases.Mesechymal stem cells (MSCs) act as the external force sensoring and compression-bearing elements.What we want to explore is how mechanical stimulation affects the genome changes of mesenchymal stem cells.
2023-11-13 | GSE247273 | GEO
Project description:The renewing human epidermis constantly senses and adapts to a wide range of mechanical cues that are ubiquitous throughout life. The mechanisms of how mechanical forces are responded by interfollicular epidermal stem cells (IFESCs) and are transmitted directly into nucleus to modify gene expression remain incompletely defined. In vitro, human IFESCs were cultured on the collagen I coated silicon rubber membrane and then subjected to the mechanical stretched. Cyclic mechanical tension at 0.5 Hz sinusoidal curve at 10% elongation was applied using an FX-5000T™ Flexercell® Tension Plus™ unit (Flexcell International Corporation). In mechanical unloading groups, cells were cultured on the same plates in the same incubator with the mechanical stretched groups but not subjected to stretch. Combining genome-wide microarray and functional analyses, we made transcriptome analysis of samples from the mechanical unstretched or stretched isolated human IFESCs.
2018-07-26 | GSE71391 | GEO
Project description:Mechanical stress by blunt force trauma elicits a distinct and reproducible transcriptional response in C. elegans. Vhp-1, a MAPK phosphatase, regulates a significant portion of these stress-inducible transcripts.
2020-04-09 | GSE148337 | GEO
Project description:We inegrated quantitative phosphoproteome, proteome, a tergeted MS analysis, in conjunction with pathway perturbation to obtain a global view of the mechano-responses of embryonic tissues. This study provides mechanistic insights into mechanical force sensing pathways.
2019-10-09 | MSV000084444 | MassIVE
Project description:Hypertrophic scar (HTS) formation is characterized by exuberant fibroproliferation for reasons that remain poorly understood1. One important but often overlooked component of wound repair is mechanical force, which regulates reciprocal cell-matrix interactions through focal adhesion components including focal adhesion kinase (FAK)1,2. Here we report that FAK is activated following cutaneous injury and that this activation is potentiated by mechanical loading. Transgenic mice lacking fibroblast-specific FAK exhibit significantly less fibrosis in a preclinical model of HTS formation. Inflammatory pathways involving monocyte chemoattractant protein-1 (MCP-1), a chemokine highly implicated in human skin fibrosis3, are triggered following FAK activation, mechanistically linking physical force to fibrosis. Further, small molecule inhibition of FAK effectively abrogates fibroproliferative mechanisms in human cells and significantly reduces scar formation in vivo. Collectively, these findings establish a molecular basis for HTS formation based on the mechanical activation of fibroblast-specific FAK and demonstrate the therapeutic potential of targeted mechanomodulatory strategies. Wildtype murine tissue was harvested at either day 6 or 14 post-injury following 48 hours or 10 days of mechanical loading, respectively (n=4 mice per group per time point). Murine RNA was isolated, labeled, and hybridized to the GeneChip microarray according to the manufacturer’s protocols (Affymetrix, Santa Clara, CA, USA). Each gene in the microarray was represented by 20 oligonucleotide pairs, with each pair consisting of an oligonucleotide perfectly matched to the cDNA sequence, and a second oligonucleotide containing a single base mismatch. Raw microarray data (sample intensity files) were processed using GeneSpring GX 11.0 (Agilent Technologies Inc., Santa Clara, CA, USA).
2011-01-14 | E-GEOD-26390 | biostudies-arrayexpress
Project description:Mechanical force is critical for lung development. In this study we identified specific EV-miRNAs released from the mouse epithelial cell line in response to mechanical stretch involve in lung development. In utero fetal lung experiences significant continuous transpulmonary pressure as a result of epithelial secretion in to the airway lumen, and periodic fetal breathing movement that move the fluid along the developing airway. Mechanical force is important factors for fetal lung development. However, the effect of mechanical force on the functions of lung cells is not known precisely. Extracellular vesicles –microRNAs (EV-miRNA) are increasingly recognized as a new mode of cell-to-cell communication. miRNA is well known as a regulator of physio-pathological process. In this study, we used oligonucleotide microarray technology to investigate miRNA expression in EV-released from mouse lung epithelial cell MLE12 after exposed to 10% cyclic or 5% continuous stretch. Analysis of microarray data identified 9 and 33 miRNAs significantly differentially expressed by the cyclic and continuous stretch respectively. Several differentially expressed miRNAs were reported dynamically expressed in mouse developing lung. miRNAs associated with important transcription factors for cell function and key signaling pathways for fetal lung development also identified in this study. We conclude that mechanical signals differentially regulate the expression of specific EV/miRNAs in MLE12 are important for intercellular communication during lung fetal development.
2019-05-23 | GSE131645 | GEO
Project description:The process of protein precipitation can be used to decipher the interaction of ligand and protein. For example, the classic Thermal Proteome Profiling (TPP) method uses heating as the driving force for protein precipitation, to discover the drug target protein. Under heating or other denature forces, the target protein that binds with the drug compound will be more resistant to precipitation than the free protein. Similar to thermal stress, mechanical stress can also induce protein precipitation. Upon mechanical stress, protein will gradually precipitate along with protein conformational changes, which can be exploited for the study of the ligand-protein interaction. Herein, we proposed a Mechanical Stress Induced Protein Precipitation (MSIPP) method for drug target deconvolution. Its streamlined workflow allows in situ sample preparation on the surface of microparticles, from protein precipitation to digestion. The mechanical stress was generated by vortexing the slurry of protein solution and microparticle materials. The mechanical stress induced protein precipitate was captured by the microparticles, which guarantees the MSIPP method to be scalable and user-friendly. The MSIPP method was successfully applied to four drug compounds, Methotrexate, Raltitrexed, SHP099, Geldanamycin and a pan-inhibitor of protein kinases, Staurosporine. Besides, DHFR was demonstrated to be a target of Raltitrexed, which has not been revealed by any other modification-free drug target discovery method yet. Thus, MSIPP is a complementary method to other drug target screening methods.
2022-06-10 | PXD025528 | JPOST Repository
Project description:Transcriptomes of differentiated cells of the conditionally immortalized mouse podocyte cell line SVI (Schiwek et al., Kidney Int. 66: 91-101, 2004) were determined as described in Warsow et al. (Kidney Int. 84: 104-115, 2013) after application of mechanical stress (Endlich et al., J. Am. Soc. Nephrol. 12: 413-422, 2001) as compared to control conditions. Elevated glomerular pressure represents a high risk for the development of severe kidney diseases and causes an increase of mechanical load to podocytes. In this study we investigated whether mechanical stress alters gene expression in cultured podocytes using gene arrays. We found that tetraspanin CD9 is significantly upregulated in cultured podocytes after mechanical stress. The differential expression of CD9 was confirmed by RT-PCR and Western blot under stretched and unstretched conditions. Furthermore, mechanical stress resulted in a relocalization of CD9. To get an insight into the functional role of CD9, podocytes were transfected with pEGFP-CD9. The expression of CD9 induced the formation of substratum-attached thin arborized protrusions (TAPs). Ca2+ depletion revealed that podocytes over-expressing CD9 possess altered adhesive properties in contrast to the control transfected cells. Finally, elevated CD9 expression increased migration of podocytes in a wound assay. In summary, our results suggest that upregulation of CD9 may play an important role in podocyte morphology, adhesion and migration. Three independent batches were used.
2015-02-27 | E-GEOD-66336 | biostudies-arrayexpress
Project description:We inegrated quantitative phosphoproteome, proteome, a tergeted MS analysis, in conjunction with pathway perturbation to obtain a global view of the mechano-responses of embryonic tissues. This study provides mechanistic insights into mechanical force sensing pathways.
2019-02-16 | PXD010676 | Pride