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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)

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Abstract

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 M2 muscarinic acetylcholine receptor (M2R), choline acetyltransferase (ChAT), and vesicular acetylcholine transporter (VAChT). M2R immunoreactivity was detected in the walls of blood vessels. As evidenced via parallel staining for CD31 and alpha-smooth muscle actin, most M2R immunoreactivity was present in the endothelium. M2R immunoreactivity also occured in tenocytes, which regularly immunoreact for vimentin. The degree of M2R 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 M2R 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.

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Acknowledgements

The authors are grateful to Ulla Hedlund and Lena Jonsson for excellent technical services and to Professor L.-E. Thornell for generous gifts of antibodies against human vimentin and alpha-smooth muscle actin.

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Authors and Affiliations

  1. Department of Integrative Medical Biology, Section for Anatomy, Umeå University, SE-901 87, Umeå, Sweden

    Dennis Bjur, Patrik Danielson & Sture Forsgren

  2. Department of Surgical and Perioperative Science, Sports Medicine, Umeå University, SE-901 87, Umeå, Sweden

    Håkan Alfredson

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  1. Dennis Bjur
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  2. Patrik Danielson
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  3. Håkan Alfredson
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  4. Sture Forsgren
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Correspondence to Sture Forsgren.

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Financial support was provided by the Faculty of Medicine at Umeå University, the Swedish National Centre for Research in Sports, and the County Council of Västerbotten.

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Bjur, D., Danielson, P., Alfredson, H. et al. 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 331, 385–400 (2008). https://doi.org/10.1007/s00441-007-0524-1

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