scholarly journals Hypoxia induces transcription of DOT1L in articular cartilage to protect against osteoarthritis

2021 ◽  
Author(s):  
Astrid De Roover ◽  
Ana Escribano ◽  
Frederique Cornelis ◽  
Chahrazad Cherifi ◽  
Leire Casas-Fraile ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Local Treatment ◽  
Joint Disease ◽  
Protective Effects ◽  
Bioinformatics Pipeline ◽  
Hypoxia Inducible Factor 1 ◽  
Joint Health ◽  
H3k79 Methylation

Osteoarthritis is the most prevalent joint disease worldwide and a leading source of pain and disability. To date, this disease lacks curative treatment as underlying molecular mechanisms remain largely unknown. The histone methyltransferase DOT1L protects against osteoarthritis, and DOT1L-mediated H3K79 methylation is reduced in human and mouse osteoarthritic joints. Thus, restoring DOT1L function seems to be critical to preserve joint health. However, DOT1L-regulating molecules and networks remain elusive, in the joint and beyond. Here, we identify transcription factors and networks that regulate DOT1L gene expression using a novel bioinformatics pipeline. Thereby, we unravel an undiscovered link between the hypoxia pathway and DOT1L. We provide unprecedented evidence that hypoxia enhances DOT1L expression and H3K79 methylation via hypoxia-inducible factor-1 alpha (HIF-1α). Importantly, we demonstrate that DOT1L contributes to the protective effects of hypoxia in articular cartilage and osteoarthritis. Intra-articular treatment with a selective hypoxia mimetic in mice after surgical induction of osteoarthritis restores DOT1L function and stalls disease progression. Collectively, our data unravel a novel molecular mechanism that protects against osteoarthritis with hypoxia inducing DOT1L transcription in cartilage. Local treatment with a selective hypoxia mimetic in the joint restores DOT1L function and could be an attractive therapeutic strategy for osteoarthritis.

scholarly journals HIF-1–dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia

2005 ◽  
Vol 202 (11) ◽  
pp. 1493-1505 ◽  
Author(s):  
Holger K. Eltzschig ◽  
Parween Abdulla ◽  
Edgar Hoffman ◽  
Kathryn E. Hamilton ◽  
Dionne Daniels ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Molecular Mechanisms ◽  
Hypoxia Inducible Factor ◽  
Nucleoside Transporter ◽  
In Vivo Models ◽  
Equilibrative Nucleoside Transporter ◽  
Hypoxia Inducible Factor 1 ◽  
And Function

Extracellular adenosine (Ado) has been implicated as central signaling molecule during conditions of limited oxygen availability (hypoxia), regulating physiologic outcomes as diverse as vascular leak, leukocyte activation, and accumulation. Presently, the molecular mechanisms that elevate extracellular Ado during hypoxia are unclear. In the present study, we pursued the hypothesis that diminished uptake of Ado effectively enhances extracellular Ado signaling. Initial studies indicated that the half-life of Ado was increased by as much as fivefold after exposure of endothelia to hypoxia. Examination of expressional levels of the equilibrative nucleoside transporter (ENT)1 and ENT2 revealed a transcriptionally dependent decrease in mRNA, protein, and function in endothelia and epithelia. Examination of the ENT1 promoter identified a hypoxia inducible factor 1 (HIF-1)–dependent repression of ENT1 during hypoxia. Using in vitro and in vivo models of Ado signaling, we revealed that decreased Ado uptake promotes vascular barrier and dampens neutrophil tissue accumulation during hypoxia. Moreover, epithelial Hif1α mutant animals displayed increased epithelial ENT1 expression. Together, these results identify transcriptional repression of ENT as an innate mechanism to elevate extracellular Ado during hypoxia.

scholarly journals Xenon Upregulates Hypoxia Inducible Factor 1 Alpha in Neonatal Rat Brain under Normoxic Conditions

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Simona Valleggi ◽  
Chirag B. Patel ◽  
Andrea O. Cavazzana ◽  
Daqing Ma ◽  
Francesco Giunta ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Hypoxia Inducible Factor ◽  
Neonatal Rat ◽  
Transcript Analysis ◽  
Sprague Dawley ◽  
Organ Protection ◽  
Minute Exposure ◽  
Hypoxia Inducible Factor 1 ◽  
Significant Difference

Xenon can induce cell and organ protection through different molecular mechanisms related to oxygen level. We explored the effect of xenon on oxygen-related signalling in the central nervous system via hypoxia inducible factor 1 alpha (HIF-1α) and mammalian target of rapamycin (mTOR). Methods. Postnatal day 7 (P7) Sprague Dawley rats were exposed to 25% oxygen/75% nitrogen (air group) or 25% oxygen/75% xenon (treatment group) for 120 min. Brains were collected immediately (transcript analysis—relative real-time polymerase chain reaction) or 24 hours (protein analysis—immunohistochemistry) after the 120-minute exposure period; peak anesthetic preconditioning has been previously identified at 24 hours post-exposure. Results. HIF-1α transcript and protein levels were found to be increased in xenon-exposed compared to air-exposed brains. Sustained nuclear translocation of the protein, accounting for an increased activity of HIF-1α, was also noted. mTOR transcript analysis revealed no significant difference between xenon-exposed and air-exposed brains immediately after the 120-minute exposure. Conclusion. Our data suggest that xenon induces the upregulation of HIF-1α transcription and translation, which may contribute to xenon's neuroprotective preconditioning effect. However, given that xenon exposure did not affect mTOR transcription, further investigation into other signalling cascades mediating xenon’s effects on HIF-1α in developing brain is warranted.

scholarly journals Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yoshiaki Ito ◽  
Tokio Matsuzaki ◽  
Fumiaki Ayabe ◽  
Sho Mokuda ◽  
Ryota Kurimoto ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Mirna Target ◽  
Hypoxia Inducible Factor ◽  
Cartilage Degeneration ◽  
Joint Disease ◽  
Cartilage Homeostasis ◽  
Elevated Expression ◽  
A Cell ◽  
Target Screening ◽  
And Function

AbstractOsteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

scholarly journals Understanding Hypoxia-Induced Gene Expression in Early Development: In Vitro and In Vivo Analysis of Hypoxia-Inducible Factor 1-Regulated Zebra Fish Insulin-Like Growth Factor Binding Protein 1 Gene Expression

2006 ◽  
Vol 26 (3) ◽  
pp. 1142-1155 ◽  
Author(s):  
Shingo Kajimura ◽  
Katsumi Aida ◽  
Cunming Duan
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Early Development ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Hypoxia Inducible Factor ◽  
Insulin Like Growth Factor ◽  
Zebra Fish ◽  
Factor Binding ◽  
Hypoxia Inducible Factor 1

ABSTRACT Insulin-like growth factor binding protein 1 (IGFBP-1) is a hypoxia-inducible gene that plays an important role in regulating embryonic growth and development under hypoxic stress. The molecular mechanisms underlying hypoxia-induced IGFBP-1 gene expression in the embryonic tissues are not well understood. Here we report that the hypoxia-inducible factor 1 (HIF-1) pathway is established in early embryogenesis and mediates hypoxia-induced IGFBP-1 expression. Hypoxia increased the HIF-1 activity, and HIF-1α overexpression or CoCl2 treatment resulted in elevated IGFBP-1 expression in zebra fish embryos. Although the zebra fish IGFBP-1 promoter contains 13 consensus hypoxia response elements (HREs), deletion and mutational analysis revealed that only the HRE positioned at −1090/−1086 is required for the hypoxia and HIF-1 induction. Further experiments revealed that there is an HIF-1 ancillary sequence (HAS) adjacent only to the functional HRE. Mutation of this HAS greatly reduced the responsiveness of the IGFBP-1 promoter to hypoxia and HIF-1. The HAS does not directly bind to HIF-1 or affect the binding of the HRE to HIF-1. The HAS is bound to a nuclear protein(s), and this HAS binding activity is reduced by hypoxia. These results suggest that HIF-1 mediates hypoxia-induced IGFBP-1 gene expression in early development by selectively interacting with the −1090/−1086 HRE and its adjacent HAS.

scholarly journals The Role of Chaperone-Mediated Autophagy in Cell Cycle Control and Its Implications in Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2140
Author(s):  
Marina Andrade-Tomaz ◽  
Izadora de Souza ◽  
Clarissa Ribeiro Reily Rocha ◽  
Luciana Rodrigues Gomes
Keyword(s):  
Cell Cycle ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Hypoxia Inducible Factor ◽  
Cellular Processes ◽  
Hypoxia Inducible Factor 1 ◽  
Chaperone Mediated Autophagy ◽  
Transformation Processes

The cell cycle involves a network of proteins that modulate the sequence and timing of proliferation events. Unregulated proliferation is the most fundamental hallmark of cancer; thus, changes in cell cycle control are at the heart of malignant transformation processes. Several cellular processes can interfere with the cell cycle, including autophagy, the catabolic pathway involved in degradation of intracellular constituents in lysosomes. According to the mechanism used to deliver cargo to the lysosome, autophagy can be classified as macroautophagy (MA), microautophagy (MI), or chaperone-mediated autophagy (CMA). Distinct from other autophagy types, CMA substrates are selectively recognized by a cytosolic chaperone, one-by-one, and then addressed for degradation in lysosomes. The function of MA in cell cycle control, and its influence in cancer progression, are already well-established. However, regulation of the cell cycle by CMA, in the context of tumorigenesis, has not been fully addressed. This review aims to present and debate the molecular mechanisms by which CMA can interfere in the cell cycle, in the context of cancer. Thus, cell cycle modulators, such as MYC, hypoxia-inducible factor-1 subunit alpha (HIF-1α), and checkpoint kinase 1 (CHK1), regulated by CMA activity will be discussed. Finally, the review will focus on how CMA dysfunction may impact the cell cycle, and as consequence promote tumorigenesis.

scholarly journals Multifaceted Protective Role of Glucosamine against Osteoarthritis: Review of Its Molecular Mechanisms

2019 ◽  
Vol 87 (4) ◽  
pp. 34 ◽  
Author(s):  
Al-Saadi ◽  
Pang ◽  
Ima-Nirwana ◽  
Chin
Keyword(s):  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Cartilage Degeneration ◽  
Redox Status ◽  
Joint Disease ◽  
Inflammatory Factors ◽  
Current Evidence ◽  
Necrosis Factor Alpha ◽  
Joint Health ◽  
Anti Inflammatory

Osteoarthritis (OA) is a joint disease resulting from cartilage degeneration and causing joint pain and stiffness. Glucosamine exerts chondroprotective effects and effectively reduces OA pain and stiffness. This review aims to summarise the mechanism of glucosamine in protecting joint health and preventing OA by conducting a literature search on original articles. Current evidence has revealed that glucosamine exhibits anti-inflammatory effects by reducing the levels of pro-inflammatory factors (such as tumour necrosis factor-alpha, interleukin-1, and interleukin-6) and enhancing the synthesis of proteoglycans that retard cartilage degradation and improve joint function. Additionally, glucosamine improves cellular redox status, reduces OA-mediated oxidative damages, scavenges free radicals, upregulates antioxidant proteins and enzyme levels, inhibits the production of reactive oxygen species, and induces autophagy to delay OA pathogenesis. In conclusion, glucosamine prevents OA and maintains joint health by reducing inflammation, improving the redox status, and inducing autophagy in joints. Further studies are warranted to determine the synergistic effect of glucosamine with other anti-inflammatory and/or antioxidative agents on joint health in humans.

scholarly journals Hypoxia-induced invadopodia formation: a role for β-PIX

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 120159 ◽  
Author(s):  
Nur Fariesha Md Hashim ◽  
Nicole S. Nicholas ◽  
Anna E. Dart ◽  
Serafim Kiriakidis ◽  
Ewa Paleolog ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Tumour Progression ◽  
Hypoxia Inducible Factor ◽  
Negative Effects ◽  
Hypoxia Inducible Factor 1 ◽  
Mechanistic Pathway ◽  
Membrane Protrusions ◽  
Extracellular Stimuli ◽  
Invadopodia Formation

During tumour progression, oxygen tension in the microenvironment surrounding tumour cells is reduced, resulting in hypoxia. It is well established that cancer cells resist the negative effects of hypoxia by inducing angiogenesis predominantly via the activity of transcription factor hypoxia-inducible factor-1 (HIF-1). However, more recently HIF-1α has also been linked to increased invasive potential, although the molecular mechanisms remain to be defined. Invasive cancer cells are thought to employ membrane protrusions, termed invadopodia, to achieve matrix degradation. While many invadopodia components have been identified, signalling pathways that link extracellular stimuli to invadopodia formation remain largely unknown. Indeed, the relationship between invadopodia formation and HIF-1α has not been explored. We now report that HIF-1α is a driver of invadopodia formation. Furthermore, we have identified an important, direct and novel link between the Rho family activator β-PIX, HIF-1α and invadopodia formation. Indeed, we find that β-PIX expression is essential for invadopodia formation. In conclusion, we identify a new HIF-1α mechanistic pathway and suggest that β-PIX is a novel downstream signalling mediator during invadopodia formation.

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