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

Emerging evidence suggests the nervous system, including the circadian timing system, influences susceptibility to osteoarthritis (OA) via direct and indirect effects. This Review describes the interactions between the brain and the joints in the context of OA, ageing, obesity and inflammation, and outlines therapeutic and research opportunities in this field. 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.