The role of metabolism in the pathogenesis of osteoarthritis

Key Points

  • Metabolism has a key role in the physiological turnover of synovial joint tissues, including articular cartilage

  • In osteoarthritis (OA), chondrocytes and cells in joint tissues other than cartilage undergo metabolic alterations and shift from a resting regulatory state to a highly metabolically active state

  • Inflammatory mediators, metabolic intermediates and immune cells influence cellular responses in the pathophysiology of OA

  • Key metabolic pathways and mediators might be targets of future therapies for OA

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.

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Figure 1: Factors underlying metabolic alterations in osteoarthritis.
Figure 2: Phenotypes of osteoarthritis.
Figure 3: Metabolism in homeostatic chondrocytes.
Figure 4: Altered metabolism in chondrocytes in osteoarthritis.

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Acknowledgements

The authors would like to acknowledge current and previous members of their laboratories and their internal and external collaborators for their contributions. We apologize to those authors whose work could not be included in this focused Review due to space and word count limitations. The work of the authors is supported by grants from the European Union 7th Framework Programme (FP7) projects FP7- HEALTH.2012.2.4.5-2 Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases 305815 (A.M.) and Marie Skłodowska-Curie scheme FP7-PEOPLE-2013-IEF CHONDRION 625746 (A.M.); Arthritis Research UK 20194 (A.M.); the Innovative Medicine Initiative, Applied Public-Private Research Enabling Osteoarthritis Clinical Headway (APPROACH) consortium 115770 (A.M. and J.S.); the European Union MSCA-RISE 734899 (O.G.); and Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER) PIE 13/00024, PI14/00016 and RIER RD16/0012/0014 (O.G.).

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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.

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Correspondence to Ali Mobasheri.

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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.

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Glossary

Glycolysis

An oxygen-independent metabolic pathway that generates two molecules of pyruvate, ATP and NADH from every one molecule of glucose, supporting the tricarboxylic acid cycle and providing intermediates for the pentose phosphate pathway, glycosylation reactions and the synthesis of biomolecules (including serine, glycine, alanine and acetyl-CoA).

Tricarboxylic acid (TCA) cycle

(Also known as the Krebs cycle) A set of connected pathways in the mitochondrial matrix, which metabolize acetyl-CoA derived from glycolysis or fatty acid oxidation, producing NADH and FADH2 for the electron transport chain and precursors for amino acid and fatty acid synthesis.

Pentose phosphate pathway

(PPP). An anabolic metabolic pathway parallel to glycolysis that branches out from glycolysis with the conversion of glucose-6-phosphate to ribose 5-phosphate and generates the reducing equivalents NADPH, ribose-5-phosphate (used in the synthesis of nucleotides and nucleic acids) and erythrose-4-phosphosphate (used in the synthesis of amino acids).

Fatty acid oxidation

A metabolic process that produces ATP from the oxidation of acetyl-CoA derived from the mobilization of fatty acids.

Inflammaging

The low-grade proinflammatory phenotype that accompanies ageing.

Warburg effect

The high utilization of glycolysis by rapidly proliferating cells and the subsequent release of lactate into the extracellular milieu; a phenomenon first described by Otto Warburg.

Metabolic syndrome

The collective term used to describe the combination of type 2 diabetes mellitus, high blood pressure, dyslipidemia and obesity.

Electron transport chain

A series of proteins in the inner mitochondrial membrane that transfer electrons from one to the other in a series of redox reactions, resulting in the movement of protons out of the mitochondrial matrix and in the synthesis of ATP.

Oxidative phosphorylation

A metabolic pathway that produces ATP from the oxidation of acetyl-CoA and the transfer of electrons to the electron transport chain via NADH and FADH2.

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Mobasheri, A., Rayman, M., Gualillo, O. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat Rev Rheumatol 13, 302–311 (2017). https://doi.org/10.1038/nrrheum.2017.50

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