Substance P accelerates hypercellularity and angiogenesis in tendon tissue and enhances paratendinitis in response to Achilles tendon overuse in a tendinopathy model

Abstract

Background Tenocytes produce substance P (SP), and its receptor (neurokinin-1 receptor (NK-1R)) is expressed throughout the tendon tissue, especially in patients with tendinopathy and tissue changes (tendinosis) including hypercellularity and vascular proliferation. Considering the known effects of SP, one might ask whether SP contributes to these changes. Objectives To test whether development of tendinosislike changes (hypercellularity and angiogenesis) is accelerated during a 1-week course of exercise with local administration of SP in an established Achilles tendinopathy model. Methods Rabbits were subjected to a protocol of Achilles tendon overuse for 1 week, in conjunction with SP injections in the paratenon. Exercised control animals received NaCl injections or no injections, and unexercised, uninjected controls were also used. Tenocyte number and vascular density, as well as paratendinous infl ammation, were evaluated. Immunohistochemistry and in situ hybridisation to detect NK-1R were conducted. Results There was a signifi cant increase in tenocyte number in the SP-injected and NaCl-injected groups compared with both unexercised and exercised, uninjected controls. Tendon blood vessels increased in number in the SP-injected group compared with unexercised controls, a fi nding not seen in NaClinjected controls or in uninjected, exercised animals. Paratendinous infl ammation was more pronounced in the SP-injected group than in the NaCl controls. NK-1R was detected in blood vessel walls, nerves, infl ammatory cells and tenocytes. Conclusions SP accelerated the development of tendinosis-like changes in the rabbit Achilles tendon, which supports theories of a potential role of SP in tendinosis development; a fact of clinical interest since SP effects can be effectively blocked. The angiogenic response to SP injections seems related to paratendinitis.

Tendons: Time to Revisit Inflammation?

“…34 It is increased following overload of the rabbit Achilles tendon 69 and also accelerates hypercellularity and angiogenesis. 43 Increased levels of glutamate, originally thought to be confined to the CNS have been documented to be present in microdialysis of symptomatic Achilles tendon tissue. 70 Furthermore, elevated levels of the glutamate receptor, N-methyl-D-aspartate receptor type 1 (NMDAR1) have also been documented in chronic tendinopathy.…”

“…For instance, when substance P is injected peritendinously, the vascularity of the tendon increases. 43 …”

Neuronal pathways in tendon healing and tendinopathy - update

“…The increase of the sensory neuropeptide SP in tendinopathy may, in addition to its role in nociception, reflect proinflammatory and trophic actions (143). Thus, SP has been found to participate in inflammatory actions such as vasodilation, plasma extravasation, and release of cytokines.…”

“…Thus, SP has been found to participate in inflammatory actions such as vasodilation, plasma extravasation, and release of cytokines. SP has also been reported to stimulate proliferation of fibroblasts (143) and endothelial cells, as well as the production of transforming growth factor beta in fibroblasts. Hence, SP may well contribute to the morphologic changes observed in early tendinopathic patients, that is, tenocyte transformation, hypercellularity, and presumably neovascularization, in conjunction with mechanical loading (37,144), and may therefore precede tendinosis.…”

Comparison of Clinical Efficacy Among Endoscopy-Assisted Radio-Frequency Ablation, Extracorporeal Shockwaves, and Eccentric Exercises in Treatment of Insertional Achilles Tendinosis

“…The first case of insertional Achilles tendinosis was reported by Clain and Baxter, 5 and they suggested that the possible cause was Haglund deformity and retrocalcaneal bursitis, whereas other investigators have proposed contrasting arguments. 6 A variety of methods have been applied in treating Achilles tendinosis, including physical therapy, injection therapy, eccentric calf muscle exercises, and extracorporeal shockwaves (ESWs). It has been shown that eccentric exercises and ESW therapy yield the highest clinical efficacy in the clinical setting.…”