Glucose-6-Phosphate Isomerase (G6PI) Mediates Hypoxia-Induced Angiogenesis in Rheumatoid Arthritis

Lü, Ying; Yu, Shanshan; Zong, Min‐Hua; Fan, Shasha; Lu, Tianbao; Gong, Ruhan; Sun, Lin; Fan, Lieying

doi:10.1038/srep40274

Cited by 44 publications

(38 citation statements)

References 41 publications

(45 reference statements)

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“…This phenomenon was accompanied by enhanced proliferation of RA FLS and angiogenic tube formation of human dermal microvascular endothelial cells (HDMECs) in vivo. These events were reversed in G6PI loss-of-function experiments, thus confirming the requirement for G6PI in promoting angiogenesis in RA (Lu et al, 2017).…”

Section: Glucose Metabolismsupporting

confidence: 57%

“…Blockade of the glycolytic enzyme, PFKFB3, inhibited angiogenic tube formation in vivo and reduced the secretion of pro-inflammatory/angiogenic mediators in RA FLS and EC suggesting a key role of this glycolytic enzyme in promoting angiogenesis and inflammation (Biniecka et al, 2016). G6PI was also found to be important in the regulation of VEGF secretion from RA FLS (Lu et al, 2017). Indeed, in hypoxic conditions, both G6PI and HIF-1α were increased.…”

Section: Glucose Metabolismmentioning

confidence: 96%

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Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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Several studies have highlighted the interplay between metabolism, immunity and inflammation. Both tissue resident and infiltrating immune cells play a major role in the inflammatory process of rheumatoid arthritis (RA) via the production of cytokines, adipocytokines and metabolic intermediates. These functions are metabolically demanding and require the most efficient use of bioenergetic pathways. The synovial membrane is the primary site of inflammation in RA and exhibits distinctive histological patterns characterized by different metabolism, prognosis and response to treatment. In the RA synovium, the high energy demand by stromal and infiltrating immune cells, causes the accumulation of metabolites, and adipo-cytokines, which carry out signaling functions, as well as activating transcription factors which act as metabolic sensors. These events drive immune and joint-resident cells to acquire pro-inflammatory effector functions which in turn perpetuate chronic inflammation. Whether metabolic changes are a consequence of the disease or one of the causes of RA pathogenesis is still under investigation. This review covers our current knowledge of cell metabolism in RA. Understanding the intricate interactions between metabolic pathways and the inflammatory and immune responses will provide more awareness of the mechanisms underlying RA pathogenesis and will identify novel therapeutic options to treat this disease.

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Section: Glucose Metabolismsupporting

confidence: 57%

Section: Glucose Metabolismmentioning

confidence: 96%

Metabolic Checkpoints in Rheumatoid Arthritis

et al. 2020

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“…In RA-FLS and EC, hypoxia induces activation of intracellular Notch-1IC and its ligand DLL-4, interaction of which is critical for EC tip cell selection, and lateral inhibition of the trailing stalk cell [13,14]. In addition, enriched expression of G6PI in synovial endothelial cells has recently been shown, with in-vitro G6PI loss-of-function assays demonstrating the requirement of G6PI in mediating hypoxia-induced angiogenesis in RA [89]. In addition, enriched expression of G6PI in synovial endothelial cells has recently been shown, with in-vitro G6PI loss-of-function assays demonstrating the requirement of G6PI in mediating hypoxia-induced angiogenesis in RA [89].…”

Section: Metabolism Of Synovial Endotheliummentioning

confidence: 98%

“…Blockade of the glycolytic enzyme, PFKFB3, inhibits angiogenic tube formation, secretion of proinflammatory/angiogenic mediators and key signalling pathways in RA-FLS and EC [21]. In addition, enriched expression of G6PI in synovial endothelial cells has recently been shown, with in-vitro G6PI loss-of-function assays demonstrating the requirement of G6PI in mediating hypoxia-induced angiogenesis in RA [89]. Finally, in animal models of arthritis, succinate has been shown to induce synovial angiogenesis through VEGF-dependent HIF-1α pathways [90].…”

Section: Metabolism Of Synovial Endotheliummentioning

confidence: 99%

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

Fearon

Hanlon

Wade

et al. 2018

Clinical and Experimental Immunology

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Rheumatoid arthritis is characterized by synovial proliferation, neovascularization and leucocyte extravasation leading to joint destruction and functional disability. The blood vessels in the inflamed synovium are highly dysregulated, resulting in poor delivery of oxygen; this, along with the increased metabolic demand of infiltrating immune cells and inflamed resident cells, results in the lack of key nutrients at the site of inflammation. In these adverse conditions synovial cells must adapt to generate sufficient energy to support their proliferation and activation status, and thus switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This alters redox-sensitive signalling pathways and also results in the accumulation of metabolic intermediates which, in turn, can act as signalling molecules that further exacerbate the inflammatory response. The RA synovium is a multi-cellular tissue, and while many cell types interact to promote the inflammatory response, their metabolic requirements differ. Thus, understanding the complex interplay between hypoxia-induced signalling pathways, metabolic pathways and the inflammatory response will provide better insight into the underlying mechanisms of disease pathogenesis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIESTranslating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experimental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity.

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“…Cells in hypoxic conditions tends to divide slowly, making them unresponsive to chemotherapeutic reagents. Hypoxia can result in the activation of genes associated with angiogenesis and cell survival [ 146 , 147 , 148 ]. Many chemotherapeutic drugs cause DNA damage through generating free radicals [ 149 , 150 , 151 ].…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

Senthebane

Rowe

Thomford

et al. 2017

IJMS

334

330

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Chemoresistance is a leading cause of morbidity and mortality in cancer and it continues to be a challenge in cancer treatment. Chemoresistance is influenced by genetic and epigenetic alterations which affect drug uptake, metabolism and export of drugs at the cellular levels. While most research has focused on tumor cell autonomous mechanisms of chemoresistance, the tumor microenvironment has emerged as a key player in the development of chemoresistance and in malignant progression, thereby influencing the development of novel therapies in clinical oncology. It is not surprising that the study of the tumor microenvironment is now considered to be as important as the study of tumor cells. Recent advances in technological and analytical methods, especially ‘omics’ technologies, has made it possible to identify specific targets in tumor cells and within the tumor microenvironment to eradicate cancer. Tumors need constant support from previously ‘unsupportive’ microenvironments. Novel therapeutic strategies that inhibit such microenvironmental support to tumor cells would reduce chemoresistance and tumor relapse. Such strategies can target stromal cells, proteins released by stromal cells and non-cellular components such as the extracellular matrix (ECM) within the tumor microenvironment. Novel in vitro tumor biology models that recapitulate the in vivo tumor microenvironment such as multicellular tumor spheroids, biomimetic scaffolds and tumor organoids are being developed and are increasing our understanding of cancer cell-microenvironment interactions. This review offers an analysis of recent developments on the role of the tumor microenvironment in the development of chemoresistance and the strategies to overcome microenvironment-mediated chemoresistance. We propose a systematic analysis of the relationship between tumor cells and their respective tumor microenvironments and our data show that, to survive, cancer cells interact closely with tumor microenvironment components such as mesenchymal stem cells and the extracellular matrix.

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Glucose-6-Phosphate Isomerase (G6PI) Mediates Hypoxia-Induced Angiogenesis in Rheumatoid Arthritis

Cited by 44 publications

References 41 publications

Metabolic Checkpoints in Rheumatoid Arthritis

Metabolic Checkpoints in Rheumatoid Arthritis

Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis

The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer

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