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The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond

Key Points

  • Osteoarthritis (OA) is an active disease of the whole joint that is subject to both local and systemic regulation

  • The nervous system controls key aspects of joint pathophysiology by regulating circadian rhythms, the hypothalamic–pituitary–adrenal axis, and metabolic and inflammatory pathways

  • Ageing, obesity and chronic inflammation interfere with the brain–joint axis (including the circadian system), which compromises joint homeostasis and increases susceptibility to OA

  • Circadian clocks in the central brain and peripheral joint tissues temporally coordinate local physiology to the daily rhythmic environment (light–dark, feeding–fasting, body temperature regulation and mechanical loading cycles)

  • Environmental or genetic disruption to the biological timing system might be a novel risk factor for OA susceptibility

  • Targeting the nervous system or circadian system could provide novel therapeutic avenues for OA

Abstract

Osteoarthritis (OA) is a prevalent and debilitating joint disease for which ageing, obesity and chronic inflammation are known risk factors. The central, peripheral and autonomic nervous systems are essential in all metabolic systems, and emerging evidence suggests a role for these systems in OA. In the past few years, metabolic diseases, such as obesity or diabetes, have been linked to disruption of circadian rhythms that are tightly regulated by the nervous system, whereas inflammatory and autoimmune diseases are known to be linked to disruption of the cholinergic vagus nerve reflex. Interestingly, metabolism, inflammation and circadian rhythms have all been linked to the development and progression of OA. This article reviews current knowledge of the direct and indirect roles of the nervous system and circadian system in the initiation and/or progression of OA, and highlights the directions for future research in this emerging field.

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Figure 1: An integrative view of the pathophysiology of OA.
Figure 2: Circadian control of tissue homeostasis within the joint.
Figure 3: The cholinergic anti-inflammatory reflex arc in OA: a working hypothesis.
Figure 4: Clock gene deregulation: a functional link between ageing and OA.

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Acknowledgements

F.B.'s work is supported by the Arthritis Foundation R&D (ROAD: Research on Osteoarthritic Diseases) and by the French Society of Rheumatology. Q.-J.M's work is supported by Arthritis Research UK and the Medical Research Council (UK).

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F.B. and Q.-J.M. researched the data for the article, contributed equally to discussions of its content, wrote the manuscript, and undertook review or editing of the manuscript before submission.

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Correspondence to Francis Berenbaum or Qing-Jun Meng.

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Berenbaum, F., Meng, QJ. The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond. Nat Rev Rheumatol 12, 508–516 (2016). https://doi.org/10.1038/nrrheum.2016.93

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