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 RHEUMATOID ARTHRITIS IN 2018

Cell metabolism as a potentially targetable pathway in RA

Nature Reviews Rheumatology volume 15, pages 70–72 (2019)Cite this article

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Cell metabolism has long been at the forefront of tumour biology, but in the past decade the importance of cellular bioenergetics has been increasingly recognized in regulating immune cell function. Mechanistic studies in 2018 have highlighted cell metabolism as a potential therapeutic target for the treatment of rheumatoid arthritis.

Key advances

  • Fibroblast-like synoviocytes are hyper-glycolytic and express large amounts of hexokinase 2 (HK2), which mediates their invasive phenotype; the blockade of HK2 represents a novel therapeutic strategy1.

  • Succinate uptake via succinate receptor GPR91 induces an angiogenic phenotype in endothelial cells through hypoxia-inducible factor 1α-mediated vascular endothelial growth factor secretion, leading to increased migration, invasion and vessel sprouting2.

  • In rheumatoid arthritis and coronary artery disease, macrophages have increased metabolic activity, a process mediated by glycogen synthase kinase 3β that depends on endoplasmic-reticulum-to-mitochondria calcium transport3.

FLSs are important stromal cells in the joint that contribute to RA pathogenesis. The invasive phenotype of FLSs facilitates the degradation and destruction of cartilage through the production of matrix metalloproteinases (MMPs), pro-inflammatory cytokines and chemokines. Previous studies examining FLS function in RA have found these cells to rely heavily on glucose and glutamine metabolism4,5. In particular, a 2016 study showed the increased glycolytic nature of FLSs from patients with RA compared with those from patients with osteoarthritis, which was characterized by an increased expression of hexokinase 2 (HK2) and glucose transporter 1 (GLUT1)6. In this study, HK2 blockade ameliorated inflammation and subsequent cartilage damage in the K/B×N serum transfer model of arthritis. These results6 set the precedent for the 2018 study by Bustamante et al.1, which further highlighted HK2 as a potential therapeutic target for RA.

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Fig. 1: Regulation of inflammation through metabolism.

References

  1. Bustamante, M. F. et al. Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis. Ann. Rheum. Dis. 77, 1636–1643 (2018).

    Article  Google Scholar 

  2. Li, Y. et al. Succinate induces synovial angiogenesis in rheumatoid arthritis through metabolic remodeling and HIF-1α/VEGF axis. Free Radic. Biol. Med. 126, 1–14 (2018).

    Article  Google Scholar 

  3. Zeisbrich, M. et al. Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation. Ann. Rheum. Dis. 77, 1053–1062 (2018).

    Article  CAS  Google Scholar 

  4. McGarry, T. et al. Resolution of TLR2-induced inflammation through manipulation of metabolic pathways in rheumatoid arthritis. Sci. Rep. 7, 43165 (2017).

    Article  CAS  Google Scholar 

  5. Takahashi, S. et al. Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 19, 76 (2017).

    Article  Google Scholar 

  6. Garcia-Carbonell, R. et al. Critical role of glucose metabolism in rheumatoid arthritis fibroblast-like synoviocytes. Arthritis Rheumatol. 68, 1614–1626 (2016).

    Article  CAS  Google Scholar 

  7. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    Article  CAS  Google Scholar 

  8. Biniecka, M. et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann. Rheum. Dis. 75, 2192–2200 (2016).

    Article  CAS  Google Scholar 

  9. Littlewood-Evans, A. et al. GPR91 senses extracellular succinate released from inflammatory macrophages and exacerbates rheumatoid arthritis. J. Exp. Med. 213, 1655–1662 (2016).

    Article  CAS  Google Scholar 

  10. Watanabe, R. et al. Glucose metabolism controls disease-specific signatures of macrophage effector functions. JCI Insight 3, 123047 (2018).

    Article  Google Scholar 

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Authors and Affiliations

  1. Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland

    Trudy McGarry & Ursula Fearon

  2. Centre for Arthritis and Rheumatic Diseases, St Vincent’s University Hospital, University College Dublin, Dublin, Ireland

    Trudy McGarry

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  1. Trudy McGarry
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  2. Ursula Fearon
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Correspondence to Ursula Fearon.

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McGarry, T., Fearon, U. Cell metabolism as a potentially targetable pathway in RA. Nat Rev Rheumatol 15, 70–72 (2019). https://doi.org/10.1038/s41584-018-0148-8

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