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

Journal name:
Nature Reviews Rheumatology
Year published:
Published online


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.

At a glance


  1. An integrative view of the pathophysiology of OA.
    Figure 1: An integrative view of the pathophysiology of OA.

    The joint is an organ that interacts with its environment. Joint homeostasis is under the control of local, humoral and neuronal factors. Dysregulation of these factors and/or an abnormal perception of them locally could provoke a joint degradation process leading to OA. Many of these factors are under the master control of the CNS (control of clock genes from the suprachiasmatic nucleus, the HPA axis, the HPT axis, vagal nerve reflex). Local factors include mechanical cues and advanced glycation end-products. Humoral factors include inflammatory cytokines and growth factors, adipose tissue humoral mediators (adipokines, fatty acids), glucose and insulin levels, and senescence-associated secretory proteins. Neuronal factors include neuromediators. ANS, autonomic nervous system; CNS, central nervous system; HPA axis, hypothalamic–pituitary–adrenal axis; HPT axis, hypothalamic–pituitary–thyroid axis; OA, osteoarthritis.

  2. Circadian control of tissue homeostasis within the joint.
    Figure 2: Circadian control of tissue homeostasis within the joint.

    Light and other environmental Zeitgebers (time cues) entrain the master clock in the suprachiasmatic nucleus (SCN). The SCN then generates endogenous circadian time cues that can be transmitted to the peripheral tissues. The peripheral tissues exhibit autonomous circadian clocks that can be entrained by the SCN not only directly (through neuronal innervation), but also indirectly through time cues coming from the environment (for example, hormones, food intake, core body temperature and physical activity). The molecular clock controls a variety of genes and pathways crucial for correct functioning of the tissues in the musculoskeletal system. Mutations of the core clock components can result in a range of pathologies affecting structural components of the tissues, energy metabolism and differentiation along tissue-specific lineages. HPA axis, hypothalamic–pituitary–adrenal axis; OA, osteoarthritis; PTH, parathyroid hormone.

  3. The cholinergic anti-inflammatory reflex arc in OA: a working hypothesis.
    Figure 3: The cholinergic anti-inflammatory reflex arc in OA: a working hypothesis.

    An inflammatory state is present in osteoarthritis (OA), produced either by the secretion of cytokines from the synovium or, in the context of obesity, indirectly from adipose tissue. These cytokines are involved in the degradation of cartilage by inducing the local secretion of MMPs and ADAMTSs via the activation of signalling pathways, mainly MAPK and NF-κB pathways. Cytokines can also activate the afferent arc of the vagus nerve. After integration of these signals at the brain level, the efferent arc is activated leading to the release of acetylcholine into the microenvironment of the chondrocyte. Acetylcholine binding to its receptors blunts MAPK and NF-kB pathways and thus inhibits cartilage degradation. This cholinergic anti-inflammatory reflex arc can also be externally activated by implanting an external device close to the vagus nerve that delivers electrical stimulation.

  4. Clock gene deregulation: a functional link between ageing and OA.
    Figure 4: Clock gene deregulation: a functional link between ageing and OA.

    During ageing, circadian rhythms deteriorate, leading to increased propensity to obesity, which is a major risk factor for metabolic osteoarthritis (OA). Disrupted circadian rhythms in old age is also associated with altered diurnal patterns and reduced levels of physical activity, further contributing to OA pathogenesis. Age-related decline of local clock functions within the joint can have more direct detrimental effects on the homeostasis of joint tissues. ANS, autonomic nervous system; HPA axis, hypothalamic–pituitary–adrenal axis; HPT axis, hypothalamic–pituitary–thyroid axis.


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  1. Rheumatology Department, Sorbonnes Universités UPMC Univ Paris 06, INSERM UMRS_938, DHU i2B, Assistance Publique-Hopitaux de Paris, Hôpital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, Paris 75012, France.

    • Francis Berenbaum
  2. Faculty of Biology, Medicine and Health, Wellcome Trust Centre for Cell Matrix Research, University of Manchester, Oxford Road, Manchester M13 9PT, UK. University of Manchester

    • Qing-Jun Meng


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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The authors declare no competing interests.

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  • Francis Berenbaum

    Francis Berenbaum is Professor of Rheumatology at Pierre & Marie Curie University and Director of the Department of Rheumatology at AP-HP Saint-Antoine Hospital in Paris, France. He leads an experimental team at INSERM institute. He was president of OARSI (Osteoarthritis Research Society International) 2008–2010. His basic research interests include the understanding of relationships between metabolic diseases and osteoarthritis (OA). His clinical research focuses on hand OA and on new targeted therapies for treating symptoms and structural changes in OA.

  • Qing-Jun Meng

    Qing-Jun Meng is a Senior Research Fellow at the University of Manchester, UK. He obtained his MD and PhD in China and underwent postdoctoral training at the Faculty of Life Sciences, University of Manchester, UK. In 2009, he was awarded a 5-year Medical Research Council Career Development Award Fellowship and started his own research group at Manchester University. In 2015, he was awarded an Arthritis Research UK Senior Research Fellowship to continue his work on the roles of molecular circadian clocks in health and disease of joint tissues.

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