Immunometabolism

The role of metabolism in the pathogenesis of osteoarthritis

Journal name:
Nature Reviews Rheumatology
Volume:
13,
Pages:
302–311
Year published:
DOI:
doi:10.1038/nrrheum.2017.50
Published online

Abstract

Metabolism is important for cartilage and synovial joint function. Under adverse microenvironmental conditions, mammalian cells undergo a switch in cell metabolism from a resting regulatory state to a highly metabolically activate state to maintain energy homeostasis. This phenomenon also leads to an increase in metabolic intermediates for the biosynthesis of inflammatory and degradative proteins, which in turn activate key transcription factors and inflammatory signalling pathways involved in catabolic processes, and the persistent perpetuation of drivers of pathogenesis. In the past few years, several studies have demonstrated that metabolism has a key role in inflammatory joint diseases. In particular, metabolism is drastically altered in osteoarthritis (OA) and aberrant immunometabolism may be a key feature of many phenotypes of OA. This Review focuses on aberrant metabolism in the pathogenesis of OA, summarizing the current state of knowledge on the role of impaired metabolism in the cells of the osteoarthritic joint. We also highlight areas for future research, such as the potential to target metabolic pathways and mediators therapeutically.

At a glance

Figures

  1. Factors underlying metabolic alterations in osteoarthritis.
    Figure 1: Factors underlying metabolic alterations in osteoarthritis.

    Poor diet and lifestyle choices can contribute to weight gain and lead to obesity. Ageing, obesity and other co-morbidities associated with osteoarthritis (OA) contribute to metabolic reprogramming in a variety of cells and tissues, leading to inflammaging and cellular senescence, which in turn cause further changes in cellular metabolism in OA.

  2. Phenotypes of osteoarthritis.
    Figure 2: Phenotypes of osteoarthritis.

    Evidence suggests that patients with osteoarthritis (OA) fall into multiple phenotypic subgroups defined on the basis of the main driver of disease, one of which is a distinct metabolic phenotype, although all OA phenotypes probably involve metabolic alterations. Cartilage, bone and synovium are all affected by external and internal drivers of disease such as inflammation, injury or biomechanical alterations, metabolic reprogramming and immunomodulation, but different synovial joint tissues dominate the disease in different patients with OA.

  3. Metabolism in homeostatic chondrocytes.
    Figure 3: Metabolism in homeostatic chondrocytes.

    In healthy joints, chondrocytes utilize glucose as well as other metabolic fuels and sources of energy. Glucose utilization via glycolysis and oxidative phosphorylation helps to maintain an optimal level of mitochondrial function and biogenesis. The metabolism of healthy chondrocytes is therefore optimized to maintain normal energy homeostasis via signalling through the AMPK–SIRT1–PGC1α pathway. AMPK, AMP-activated protein kinase; ETC, electron transport chain; GLUT1, glucose transporter type 1; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1α; ROS, reactive oxygen species; SIRT1, NAD-dependent protein deacetylase sirtuin-1; TCA, tricarboxylic acid.

  4. Altered metabolism in chondrocytes in osteoarthritis.
    Figure 4: Altered metabolism in chondrocytes in osteoarthritis.

    Chondrocytes in osteoarthritis (OA) switch from oxidative phosphorylation to glycolysis as their main source of energy metabolism. In osteoarthritic joints, chondrocytes are exposed to proinflammatory cytokines and microenvironmental alterations, including hypoxia and nutrient stress. Mitochondrial metabolism is impaired and reactive oxygen species (ROS) accumulate, causing damage to mitochondria which inhibits AMPK signalling and activity, downregulate SIRT1 and decrease levels of PGC1α, the master regulator of mitochondrial biogenesis. AMPK, AMP-activated protein kinase; ETC, electron transport chain; GLUT1, glucose transporter type 1; PGC1α, peroxisome proliferator-activated receptor γ co-activator 1α; SIRT1, NAD-dependent protein deacetylase sirtuin-1; TCA, tricarboxylic acid.

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Affiliations

  1. Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical Sciences University of Surrey, Guildford GU2 7AL, UK.

    • Ali Mobasheri
  2. Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis and MRC Arthritis Research UK Centre for Musculoskeletal Ageing Research, Queen's Medical Centre, Nottingham NG7 2UH, UK.

    • Ali Mobasheri
  3. Department of Nutritional Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, UK.

    • Margaret P. Rayman
  4. SERGAS (Servizo Galego de Saude) and IDIS (Instituto de Investigación Sanitaria de Santiago), The NEIRID Group (Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases), Santiago University Clinical Hospital, Building C, Travesia da Choupana S/N, Santiago de Compostela 15706, Spain.

    • Oreste Gualillo
  5. Department of Rheumatology, Inflammation–Immunopathology–Biotherapy Department (DHU i2B), Saint-Antoine Hospital, Assistance Publique-Hôpitaux de Paris (APHP), 184 Rue de Faubourg Saint-Antoine, 75012 Paris, France.

    • Jérémie Sellam
  6. Inflammation–Immunopathology–Biotherapy Department (DHU i2B), INSERM, UMR S938, Sorbonne University, University of Paris 6, 75005 Paris, France.

    • Jérémie Sellam
  7. Department of Rheumatology, Experimental Rheumatology, Radboud University Medical Center, Geert Grooteplein 26–28, 6500 HB Nijmegen, Netherlands.

    • Peter van der Kraan
  8. Department of Molecular Rheumatology, Trinity College Dublin, University of Dublin, College Green, Dublin 2, Ireland.

    • Ursula Fearon

Contributions

All authors researched the data for the article, provided a substantial contribution to discussions of the content, contributed to writing the article and reviewed and/or edited the manuscript before submission.

Competing interests statement

A.M. declares that he has served as a Scientific Advisory Board Member for AbbVie and has received honoraria from AbbVie and Bioiberica. J.S. declares that he has served as a Scientific Advisory Board Member for AbbVie, BMS, MSD and Roche. The other authors declare no competing interests.

Corresponding author

Correspondence to:

Author details

  • Ali Mobasheri

    Ali Mobasheri is Professor of Musculoskeletal Physiology at the University of Surrey, Guildford, UK. He gained his BSc (Hons) in Biochemistry from Imperial College, London, UK, his MSc in Physiology and Biochemistry from the University of Toronto, Canada and his PhD in Molecular and Cellular Physiology from the University of Oxford, UK. He served as Associate Dean for Research and Enterprise at the University of Surrey from August 2015 to January 2017. He coordinates the European Union 7th Framework Programme funded D-BOARD consortium, is a participating member of the APPROACH Innovative Medicines Initiative consortium and is a member of the Osteoarthritis Research Society International (OARSI) Board of Directors. He will assume the position of OARSI President-Elect in April 2017.

  • Margaret P. Rayman

    Margaret P. Rayman is Professor of Nutritional Medicine at the University of Surrey, Guildford, UK and Visiting Professor and Honorary Director of the Clinical Research Centre at the First Affiliated Hospital, Xi'an Jiaotong University School of Medicine, Xi'an, China. She gained her first-class honours degree in Chemistry from Queen's University, Belfast, UK and her PhD in Inorganic Biochemistry from the University of Oxford, UK. She went on to complete postdoctoral fellowships at the Institute of Cancer Research and Imperial College, both in London, UK. She is now a Thomson-Reuters Highly Cited Researcher and her research focuses on the effects of specific micronutrient deficiencies in human health.

  • Oreste Gualillo

    Oreste Gualillo obtained his PharmD and PhD in Pharmacology at the University of Naples Federico II, Italy. He completed his training in Molecular Endocrinology at the Necker School of Medicine, Paris, France, and in the Department of Physiology and Medicine, University of Santiago de Compostela, Spain, where he was a Marie Curie Researcher funded by the European Commission. He is currently a staff researcher in the Spanish National Health System at Servizo Galego de Saude (SERGAS) and Head of the Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases (NEIRID) in Instituto de Investigación Sanitaria de Santiago (IDIS) at Santiago University Clinical Hospital, Spain.

  • Jérémie Sellam

    Jérémie Sellam is Professor of Rheumatology at Pierre et Marie Curie Paris 6 University and Saint-Antoine Hospital, Paris, France, a role he has held since 2014. He is also a researcher at the Institut National de la Santé et de la Recherche Médicale (INSERM), focusing on osteoarthritis and rheumatoid arthritis. One of his fields of interest is the role of obesity, type 2 diabetes mellitus and metabolism in rheumatoid arthritis and osteoarthritis pathophysiology and outcomes.

  • Peter van der Kraan

    Peter M. van der Kraan is Head of Experimental Rheumatology at Radboud University Medical Centre, Nijmegen, Netherlands. He has a special interest in the role of growth factors (for example, transforming growth factor-β, bone morphogenic proteins and Wnts) in rheumatic diseases such as osteoarthritis and systemic sclerosis. His research is focused on elucidation of the mechanisms of tissue destruction and application of this knowledge in the prevention of tissue damage and the stimulation of repair. He is a member of the Osteoarthritis Research Society International (OARSI) Board of Directors.

  • Ursula Fearon

    Ursula Fearon is Professor of Molecular Rheumatology at Trinity College Dublin, Republic of Ireland. She has established an international reputation for her research in the areas of synovial pathology, hypoxia, angiogenesis, metabolism and synovial fibroblast invasion, and has published extensively in this field. She is the Arthritis Ireland Head of Molecular Rheumatology at Trinity College Dublin and is part of the EULAR Centre for Rheumatology Excellence in Dublin.

Additional data