Presence of a non-neuronal cholinergic system and occurrence of up- and down-regulation in expression of M2 muscarinic acetylcholine receptors: new aspects of importance regarding Achilles tendon tendinosis (tendinopathy)

Cell Tissue Res. 2008 Feb;331(2):385-400. doi: 10.1007/s00441-007-0524-1. Epub 2007 Nov 13.


Limited information is available concerning the existence of a cholinergic system in the human Achilles tendon. We have studied pain-free normal Achilles tendons and chronically painful Achilles tendinosis tendons with regard to immunohistochemical expression patterns of the M(2) muscarinic acetylcholine receptor (M(2)R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M(2)R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M(2)R immunoreactivity was present in the endothelium. M(2)R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M(2)R immunoreactivity was highly variable, tendinosis tendons that exhibit hypercellularity and hypervascularity showing the highest levels of immunostaining. Immunoreaction for ChAT and VAChT was detected in tenocytes in tendinosis specimens, particularly in aberrant cells. In situ hybridization revealed that mRNA for ChAT is present in tenocytes in tendinosis specimens. Our results suggest that autocrine/paracrine effects occur concerning the tenocytes in tendinosis. Up-regulation/down-regulation in the levels of M(2)R immunoreactivity possibly take place in tenocytes and blood vessel cells during the various stages of tendinosis. The presumed local production of acetylcholine (ACh), as evidenced by immunoreactivity for ChAT and VAChT and the detection of ChAT mRNA, appears to evolve in response to tendinosis. These observations are of importance because of the well-known vasoactive, trophic, and pain-modulating effects that ACh is known to have and do unexpectedly establish the presence of a non-neuronal cholinergic system in the Achilles tendon.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Achilles Tendon* / anatomy & histology
  • Achilles Tendon* / metabolism
  • Achilles Tendon* / pathology
  • Adult
  • Cell Communication / physiology*
  • Choline O-Acetyltransferase / genetics
  • Choline O-Acetyltransferase / metabolism
  • Cholinergic Fibers / metabolism*
  • Down-Regulation
  • Female
  • Humans
  • In Situ Hybridization
  • Male
  • Middle Aged
  • Receptor, Muscarinic M2 / genetics
  • Receptor, Muscarinic M2 / metabolism*
  • Tendinopathy / metabolism*
  • Tendinopathy / pathology
  • Up-Regulation
  • Vesicular Acetylcholine Transport Proteins / genetics
  • Vesicular Acetylcholine Transport Proteins / metabolism


  • Receptor, Muscarinic M2
  • Vesicular Acetylcholine Transport Proteins
  • Choline O-Acetyltransferase