DRU SIN 28 /04 /2015

UNIVERSITY OF CAPE TOWNBIOLOGY OF MUSCULOSKELETAL SOFT TISSUE INJURIES THEMATIC SEMINAR

Neurogenic Hypothesis of Tendon ‘Overuse’ Injury

Terminology

Tendon

Tendinopathy

Matrix

Substance P

Innervated

Background into Tendinopathy

Literature is dominated by two hypotheses on the cause of tendon rupture: Mechanical theory Vascular theory

It is generally assumed that tendon matrix damage is the primary event causing tendinopathy, overwhelming the ability of the resident cell population to repair structural defects.

Because cell activity is required for the maintenance of connective tissues, it is equally possible that changes in cell metabolism—more specifically, the synthesis and degradation of the extracellular matrix—can influence the structural properties of the tendon.

Despite many elegant hypotheses and in vitro studies, the factors that induce pathological matrix remodelling in tendinopathy have not been fully characterized.

Neural Hypothesis

Those with a sedentary lifestyle still get affected. Why? Put forward by Khan et al. in 2000

Suggested biochemical mediators in the tendon tissue might influence or irritate nociceptors in or around the tendon

Sensory afferent nerve fibres and present in the tendon tissue Possibly sympathetic nerve ending as well? Danielson suggests possibility of nerve secretions of

catecholamines resulting in tendinopathy and pain OR from tenocytes

Tenocytes contain biosynthetic enzymes for catecholamines and acetylcholine (ACh)

SP and VGluT2 (indirect marker for glutamate release) found in tendons

Nerves contains markers for both SP and glutamate SP and glutamate are known to be pain mediators

Neural Hypothesis – Role in vascularity?

Blood vessel walls of human tendons express receptors for Catecholamines α1, α2A, and β1

ACh SP

Increased vascularity in tendon areas with structural changesAssociation found between degree of vascularity and painRole of signal substances in vasoregulation via agiogenesis?

ACh – vasodilator Stimulation α1 and α2A adrenoreceptors mediates constriction of blood

vessels Stimulation of β1 adrenoreceptors mediates relaxation of blood vessels SP shown to exert vasoregulatory effects

Neural Hypothesis

Signal substances may target tenocytes – autocrine of paracrine fashion?

Tenocytes express receptors for ACh, SP and catecholamines

Evidence: ACh and and norepinephrine can stimulate proliferation of

cells in mice and induce gene expression of collagen Stimulation of ACh receptors may augment collagen

accumulation Agonists of Ach receptors can stimulate angiogenesis and

increase collagen deposition during wound healing of the skin

SP shown to stimulate angiogenesis

Neural Hypothesis

Neurogenic hypothesis of tendon ‘overuse’ injury.

Nerve endings and mast

cells in the matrix exist as functional units in the tendon matrix. The release of neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP) stimulates the degranulation of mast cells, releasing a panoply of agents which modulate a variety of cell activities in the matrix.

Neural Hypothesis

Nerve and mast cell units function to modulate homeostatic and adaptive responses in the normal tendon, although excessive stimulation leads to tissue breakdown and degeneration.

The Neural Theory

More recently a possible neural aetiology for tendinopathy has been explored. This has been based on a number of separate observations:

The fact that tendons are innervated.

The close association within tendons of nerve cell endings and mast cells. This raises the possibility of neurally mediated mast cell degranulation and release of mediators such as substance P (a nociceptive neurotransmitter) and calcitonin gene related peptide. Chronic tendon overuse could, therefore, lead to excessive neural stimulation and result in mast cell degranulation.

That increased levels of substance P have been found in rotator cuff tendinopathy. The fact that substance P has been implicated as a pro- inflammatory mediator. The finding of glutamate, a neurotransmitter, within the ultradialysate in Achilles tendinopathy. An association between radiculopathy and tendon disorders.

Maffulli et al. [74] found an association between Achilles tendinopathy requiring surgery and sciatica in a study using peer-nominated controls.

Chronic Tendon Pain

Speculated that biochemical mediators in the tendon tissue might influence or irritate nociceptors in or around the tendon.

A traditional theory regarding the cause of the pain is that pain derives from the separation of collagen fibres in severe cases of tendinopathy, but this suggestion has been heavily contradicted with convincing arguments by Khan et al.

There are sensory afferents present in the tendon tissue, a tissue previously thought to be hyponeural, although the presence of such afferents seems very sparse in deep parts of the actual tendon tissue proper (most nerves instead being found in the loose paratendinous connective tissue surrounding the tendon).

Nerves in tendon tissue express receptors for both SP (neurokinin-1 receptor) and glutamate (NMDAR1), and that both SP32 and glutamate are known to be mediators of pain.

Theories on the aetiology of Tendinopathy

Theories on the aetiology of Tendinopathy

References

Hart DA, Frank CB, Bray RC. Inflammatory processes in repetitive motion and overuse syndromes: potential role of neurogenic mech- anisms in tendons and ligaments. In: Gordon SL, Blair SJ, Fine LJ, eds. Repetitive motion disorders of the upper extremity. Rosemont: American Academy of Orthopaedic Surgeons, 1995:247–62.

Gotoh M, Hamada K, Yamakawa H, Inoue A, Fukuda H. Increased substance P in subacromial bursa and shoulder pain in rotator cuff diseases. J Orthop Res 1998;16:618–21.

Garrett NE, Mapp PI, Cruwys SC, Kidd BL, Blake DR. Role of substance P in inflammatory arthritis. Ann Rheum Dis 1992; 51:1014–8.

Alfredson H, Thorsen K, Lorentzon R. In situ microdialysis in tendon tissue: high levels of glutamate, but not prostaglandin E2 in chronic Achilles tendon pain. Knee Surg Sports Traumatol Arthrosc 1999;7:378–81.

Maffulli N, Irwin AS, Kenward MG, Smith F, Porter RW. Achilles tendon rupture and sciatica: a possible correlation. Br J Sports Med 1998;32:174–7.