Abstract
It has been hypothesised that substance P (SP) may be produced by primary fibroblastic tendon cells (tenocytes), and that this production, together with the widespread distribution of the neurokinin-1 receptor (NK-1 R) in tendon tissue, could play an important role in the development of tendinopathy, a condition of chronic tendon pain and thickening. The aim of this study was to examine the possibility of endogenous SP production and the expression of NK-1 R by human tenocytes. Because tendinopathy is related to overload, and because the predominant tissue pathology (tendinosis) underlying early tendinopathy is characterized by tenocyte hypercellularity, the production of SP in response to loading/strain and the effects of exogenously administered SP on tenocyte proliferation were also studied. A cell culture model of primary human tendon cells was used. The vast majority of tendon cells were immunopositive for the tenocyte/fibroblast markers tenomodulin and vimentin, and immunocytochemical counterstaining revealed that positive immunoreactions for SP and NK-1 R were seen in a majority of these cells. Gene expression analyses showed that mechanical loading (strain) of tendon cell cultures using the FlexCell© technique significantly increased the mRNA levels of SP, whereas the expression of NK-1 R mRNA decreased in loaded as compared to unloaded tendon cells. Reduced NK-1 R protein was also observed, using Western blot, after exogenously administered SP at a concentration of 10−7 M. SP exposure furthermore resulted in increased cell metabolism, increased cell viability, and increased cell proliferation, all of which were found to be specifically mediated via the NK-1 R; this in turn involving a common mitogenic cell signalling pathway, namely phosphorylation of ERK1/2. This study indicates that SP, produced by tenocytes in response to mechanical loading, may regulate proliferation through an autocrine loop involving the NK-1 R.
Highlights
Despite recent scientific advances, the mechanisms of chronic tendon pain and thickening, tendinopathy, are yet not fully understood
In our recent studies of human Achilles tendon tissue, we showed that tenocytes express the mRNA for substance P (SP) (TAC1) [11], and that the preferred SP receptor is widely distributed in human tendons, with more marked expression in tendinosis tissue [11,17]
The majority of the cells were immunopositive for the tenocyte/ fibroblast markers tenomodulin (Fig. 3a) and vimentin (Fig. 3b, Fig. 4a)
Summary
The mechanisms of chronic tendon pain and thickening, tendinopathy, are yet not fully understood. It is widely accepted that the underlying tissue changes of tendinopathy, commonly thought to be induced by mechanical overload, constitute a non-inflammatory pathology (tendinosis) characterized by hypercellularity and capillary proliferation [1], but the pathogenesis remains unclear. Evidence in favour of a new theory of tendinosis pathophysiology has been presented; this hypothesis suggests that signal substances traditionally thought to be confined to neurons are produced by the tendon tissue itself and are involved in the development of tendinosis [2,3]. SP, primarily known for its involvement in afferent pain mechanisms, has efferent effects which may play a role in tendon pathology, such as stimulation of angiogenesis [12]. The immunoreactivity for nerve-related SP is increased in a rat model of Achilles tendon overuse [15], and human Achilles tendinosis is associated with sprouting of SP positive nerve fibres [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
