Neuronal pathways in tendon healing and tendinopathy--update.

The regulatory mechanisms involved in tendon homeostasis and repair are not fully understood. Accumulating data, however, demonstrate that the nervous system, in addition to afferent (sensory) functions, through efferent pathways plays an active role in regulating pain, inflammation, and tissue repair. In normal-, healing- and tendinopathic tendons three neurosignalling pathways consisting of autonomic, sensory and glutamatergic neuromediators have been established. In healthy tendons, neuromediators are found in the paratenon, whereas the proper tendon is practically devoid of nerves, reflecting that normal tendon homeostasis is regulated by pro- and anti-inflammatory mediators from the tendon surroundings. During tendon repair, however, there is extensive nerve ingrowth into the tendon proper and subsequent time-dependent appearance of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and tendon regeneration. In tendinopathy, excessive and protracted sensory and glutamatergic signalling may be involved in inflammatory, painful and hypertrophic tissue reactions. As our understanding of these processes improves, neuronal mediators may prove to be useful in the development of targeted pharmacotherapy and tissue engineering approaches to painful, degenerative and traumatic tendon disorders.