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The human Achilles tendon: innervation and intratendinous production of nerve signal substances - of importance in understanding the processes of Achilles tendinosis
Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Sports Medicine. Umeå University, Faculty of Medicine, Integrative Medical Biology, Anatomy.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Tendinopathies are painful tendon conditions of presumably multifactorial genesis. In tendinosis, as in Achilles tendinosis, there is apart from pain also morphological changes which are described as degenerative with no signs of inflammation. The exact mechanisms behind these conditions are still, to a large extent, unknown. Pain, being the foremost impairing symptom, leads us to the hypothesis that nerves are deeply involved in the symptoms and processes of Achilles tendinosis. Locally produced nerve signal substances may also be involved in the processes. Knowledge of the innervation patterns within the tendon and knowledge on a possible local nerve signal substance production are therefore of utmost importance. There is a lack of information on these aspects.

The specific aims of this thesis were 1) to investigate the innervation patterns regarding general, sensory, cholinergic and sympathetic innervations, and 2) to examine for the possible occurrence of a production of nerve signal substances and a presence of receptors related to these in the tendon cells, the tenocytes. Painfree normal and tendinosis Achilles tendons were examined.

Immunohistochemistry, using antibodies against the general nerve marker PGP9.5, the synthesizing enzymes for acetylcholine (choline acetyltransferase; ChAT), and catecholamines (tyrosine hydroxylase; TH), the vesicular acetylcholine transporter (VAChT), neuropeptide Y (NPY), substance P and calcitonin gene-related peptide, was applied. Immunohistochemistry was also used for the delineation of muscarinic (M2R), adrenergic (α1-AR) and NPY-ergic (Y1 and Y2) receptors. To detect mRNA for TH and ChAT, in situ hybridization was used.

In normal Achilles tendons, as well as in the tendinosis tendons, there was a very scanty innervation within the tendon tissue proper, the main general, sensory and sympathetic innervations being found in the paratendinous loose connective tissue. Interestingly, the tenocytes showed immunoreactions for ChAT, VAChT, TH, M2R, α1-AR and Y1R. The reactions were clearly more observable in tendons of tendinosis patients than in those of controls. The tenocytes of tendinosis patients also displayed mRNA reactions for ChAT and TH. Nevertheless, all tenocytes in the tendinosis specimens did not show these reactions. Immunoreactions for α1-AR, M2R and Y1R were also seen for blood vessel walls.

The present thesis shows that there is a very limited innervation within tendon tissue proper, whilst there is a substantial innervation in the paratendinous loose connective tissue. It also gives evidence for an occurrence of production of catecholamines and acetylcholine in tenocytes, especially for tendinosis tendons. Furthermore, that ACh, catecholamines and NPY can have effects on these, as well as on blood vessels, via the receptors observed.

The observations suggest that Achilles tendon tissue, whilst containing a very scarce innervation, exhibits autocrine/paracrine cholinergic/catecholaminergic/NPY-ergic effects that are upregulated in tendinosis. These findings are of great importance as the results of such effects may mimic processes that are known to occur in tendinosis. That includes effects related to proliferation and angiogenesis, and blood vessel and collagen regulating effects.

In conclusion, within the Achilles tendon there is a very scarce innervation, whilst there appears to be a marked local production of nerve signal substances in Achilles tendinosis, namely in the tenocytes, the cells also harbouring receptors for these substances. The observations give a new insight into how the tendon tissue of the Achilles tendon is influenced by signal substances and may give options for new treatments of Achilles tendinosis.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2010. , 88 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1321
Keyword [en]
Achilles tendon, tendinosis, tendinopathy, nerve signal substances
Keyword [sv]
hälsena, Achillessena, tendinos, tendinopati
National Category
Surgery
Research subject
Human Anatomy
Identifiers
URN: urn:nbn:se:umu:diva-30284ISBN: 978-91-7264-929-3 (print)OAI: oai:DiVA.org:umu-30284DiVA: diva2:281380
Public defence
2010-01-15, Biologihuset, sal BiA201, Umeå universitet, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2009-12-23 Created: 2009-12-15 Last updated: 2009-12-23Bibliographically approved
List of papers
1. The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation
Open this publication in new window or tab >>The innervation pattern of the human Achilles tendon: studies of the normal and tendinosis tendon with markers for general and sensory innervation
2005 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 320, no 1, 201-206 p.Article in journal (Refereed) Published
Abstract [en]

Pain-free normal Achilles tendons and chronic painful Achilles tendons were examined by the use of antibodies against a general nerve marker (protein gene-product 9.5, PGP9.5), sensory markers (substance P, SP; calcitonin gene-related peptide, CGRP), and immunohistochemistry. In the normal tendons, immunoreactions against PGP9.5 and against SP/CGRP were encountered in the paratendinous loose connective tissue, being confined to nerve fascicles and to nerve fibers located in the vicinity of blood vessels. To some extent, these immunoreactions also occurred in the tendon tissue proper. Immunoreaction against PGP9.5 and against SP/CGRP was also observed in the tendinosis samples and included immunoreactive nerve fibers that were intimately associated with small blood vessels. In conclusion, Mechanoreceptors (sensory corpuscles) were occasionally observed, nerve-related components are present in association with blood vessels in both the normal and the tendinosis tendon.

Place, publisher, year, edition, pages
Berlin / Heidelberg: Springer, 2005
Keyword
Achilles Tendon/blood supply/injuries/*innervation/*pathology/surgery, Adult, Antibodies/metabolism, Biological Markers/*analysis, Biopsy, Calcitonin Gene-Related Peptide/metabolism, Female, Humans, Male, Middle Aged, Substance P/metabolism, Ubiquitin Thiolesterase/metabolism
National Category
Surgery
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-30280 (URN)10.1007/s00441-004-1014-3 (DOI)
Available from: 2009-12-15 Created: 2009-12-15 Last updated: 2010-08-12Bibliographically approved
2. 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)
Open this publication in new window or tab >>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)
2008 (English)In: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 331, no 2, 385-400 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-8140 (URN)10.1007/s00441-007-0524-1 (DOI)17999088 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2010-06-23Bibliographically approved
3. Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon
Open this publication in new window or tab >>Immunohistochemical and in situ hybridization observations favor a local catecholamine production in the human Achilles tendon
2008 (English)In: Histology and Histopathology, ISSN 0213-3911, Vol. 23, no 2, 197-208 p.Article in journal (Refereed) Published
Abstract [en]

Results of recent studies using immunohistochemistry show evidence of an occurrence of catecholamine production in the cells (tenocytes) of patellar tendons exhibiting tendinopathy (tendinosis). In the present study, antibodies against the catecholamine-synthesizing enzyme tyrosine hydroxylase (TH) and alpha1-adrenoreceptors were applied to sections of specimens of normal and tendinosis Achilles tendons. In situ hybridization using a probe detecting human TH mRNA was also utilized. It was found that sympathetic innervation was very scarce. On the other hand, there were distinct alpha1-adrenoreceptor immunoreactions in blood vessel walls. Interestingly, tenocytes, particularly from tendinosis samples in which the tenocytes showed an abnormal shape (not the typical slender appearance), displayed TH immunoreactions and reactions for TH mRNA. Of further interest was the finding of alpha1-adrenoreceptor immunoreactions in tenocytes. The observations show not only evidence of local catecholamine production at the protein level, which was the case in recent studies for the patellar tendon, but also at the mRNA level. The observations suggest that the tenocytes, especially those with disfigured appearances in tendinosis, can produce catecholamines and also that they can respond to sympathetic transmitters. This is of interest as adrenergic stimulation in other parts of the body is known to induce degenerative/apoptotic and proliferative events, features which are seen in Achilles tendinosis. These observations are completely new findings concerning the human Achilles tendon. It is likely that locally produced catecholamines and the occurrence of autocrine/paracrine effects of these substances are of great relevance during the process of tendinosis.

Keyword
Achilles Tendon/innervation/*metabolism, Adult, Biopsy, Catecholamines/genetics/*metabolism, Female, Gene Expression, Gene Expression Regulation, Humans, Immunohistochemistry/*methods, In Situ Hybridization/*methods, Male, Middle Aged, Neuropeptide Y/metabolism, RNA; Messenger/metabolism, Receptors; Adrenergic; alpha-1/genetics/metabolism, Sympathetic Nervous System, Tendinopathy/*metabolism/pathology/surgery, Tyrosine 3-Monooxygenase/genetics/metabolism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-8141 (URN)17999376 (PubMedID)
Available from: 2008-01-15 Created: 2008-01-15 Last updated: 2010-06-23Bibliographically approved
4. Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon
Open this publication in new window or tab >>Presence of the neuropeptide Y 1 receptor in tenocytes and blood vessel walls in the human Achilles tendon
2009 (English)In: British Journal of Sports Medicine, ISSN 0306-3674, E-ISSN 1473-0480, Vol. 43, no 13, 1136-1142 p.Article in journal (Refereed) Published
Abstract [en]

Background: There are still questions concerning the mechanisms of development of chronic pain and impaired function of tendons (tendinosis). Aspects that are known to occur are cell proliferation, angiogenesis and altered blood flow regulation. Neuropeptide NPY (NPY) is widely distributed in the body and has powerful effects in relation to these processes. NPY has its effects via the G-protein-coupled Y receptors. There is no information concerning the presence or absence of NPY receptors in Achilles tendons or other tendons.

Objective: To clarify the expression patterns of the NPY receptors Y1 and Y2 in normal and tendinosis Achilles tendons of man.

Methods: Immunohistochemical methods were used. Examination on NPY was carried out in parallel.

Results: The tenocytes showed strong immunoreactions for the Y1 receptor. The immunoreactions were more intense in the tenocytes of the tendinosis tendons than in those of the non-tendinosis tendons. The rounded/oval tenocytes typically seen in tendinosis tendons exhibited marked Y1 receptor reactions on their exterior. Pronounced Y1 reactions were seen in the smooth muscle of the arterioles of both tendinosis and non-tendinosis tendons. No reactions for the Y2 receptor were noted. NPY was detected in nerve fascicles and in the perivascular innervation.

Conclusions: The present study shows that there is a morphologic correlate for the occurrence of pronounced NPY effects via the Y1 receptor in both tenocytes, this especially being a fact for tendinosis tendons, and blood vessel walls in the Achilles tendon. The findings are of particular interest as NPY is known to have proliferative, angiogenic and blood vessel regulating effects. The effects of targeting the Y1 receptor in tendinosis is an interesting task to be further evaluated.

Place, publisher, year, edition, pages
BMJ Publishing Group, 2009
National Category
Medical and Health Sciences
Research subject
Human Anatomy
Identifiers
urn:nbn:se:umu:diva-30282 (URN)10.1136/bjsm.2008.055780 (DOI)
Available from: 2009-12-15 Created: 2009-12-15 Last updated: 2012-10-10Bibliographically approved

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