Disentangling the Gordian Knot of parasympathetic innervations in arthritic joint

Healthy synovial joints receive innervations exclusively from sensory and sympathetic axons. In arthritis, however, they acquire cholinergic innervations with parasympathetic effects. The origin of cholinergic fibres in inflamed joints remains elusive. Based on clinical and preclinical evidence, we propose two models explaining their rise: (1) through sprouting and invasion of cholinergic sympathetic or parasympathetic axons from the periosteum of juxta-articular bones and (2) via phenotypic switch of intrinsic sympathetic (norepinephrinergic) fibres of synovial joints to cholinergic. The widely acknowledged anti-inflammatory and immunosuppressants effects of parasympathetic drive suggests a protective role of the newly aquired cholinergic innervations in arthritic joints. [Abstract copyright: Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.]