A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function

Rubina Aktar, Madusha Peiris, Asma Fikree, Simon Eaton, Stamatiki Kritas, Stephen J. Kentish, Eduardo J.A. Araujo, Cristiano Bacarin, Amanda J. Page, Nicol C. Voermans, Qasim Aziz, L. Ashley Blackshaw

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints to maintain correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalised by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in mouse-model. Our translational studies suggest abnormal gastric sensory function may explain upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities which will enable better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-Baclofen could be beneficial in patients. These hypotheses need confirmation through targeted clinical-trials.

ABSTRACT: Tenascin X (TNX) is a glycoprotein that regulates tissue structure through anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers Danlos Syndrome (hEDS) involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal (GI) dysfunction. Previously, we have shown TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We set out to identify if TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice suggesting vagal afferent responses are likely due to altered peripheral mechanosensitivity. In TNXB-deficient patients significantly greater symptoms of reflux, indigestion, and abdominal pain was reported. Here we report the first role for TNX in gastric function and further studies are required in TNX deficient patients to determine if symptoms can be relieved using GABAB agonists. This article is protected by copyright. All rights reserved.

LanguageEnglish
JournalJournal of Physiology
Early online date3 Jan 2019
DOIs
Publication statusPublished - 3 Jan 2019

Keywords

  • enteric neurons
  • Gastric emptying
  • gastric hypersensitivity

ASJC Scopus subject areas

  • Physiology

Cite this

Aktar, R., Peiris, M., Fikree, A., Eaton, S., Kritas, S., Kentish, S. J., ... Blackshaw, L. A. (2019). A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function. Journal of Physiology. https://doi.org/10.1113/JP277195
Aktar, Rubina ; Peiris, Madusha ; Fikree, Asma ; Eaton, Simon ; Kritas, Stamatiki ; Kentish, Stephen J. ; Araujo, Eduardo J.A. ; Bacarin, Cristiano ; Page, Amanda J. ; Voermans, Nicol C. ; Aziz, Qasim ; Blackshaw, L. Ashley. / A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function. In: Journal of Physiology. 2019.
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abstract = "KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints to maintain correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalised by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in mouse-model. Our translational studies suggest abnormal gastric sensory function may explain upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities which will enable better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-Baclofen could be beneficial in patients. These hypotheses need confirmation through targeted clinical-trials.ABSTRACT: Tenascin X (TNX) is a glycoprotein that regulates tissue structure through anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers Danlos Syndrome (hEDS) involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal (GI) dysfunction. Previously, we have shown TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We set out to identify if TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice suggesting vagal afferent responses are likely due to altered peripheral mechanosensitivity. In TNXB-deficient patients significantly greater symptoms of reflux, indigestion, and abdominal pain was reported. Here we report the first role for TNX in gastric function and further studies are required in TNX deficient patients to determine if symptoms can be relieved using GABAB agonists. This article is protected by copyright. All rights reserved.",
keywords = "enteric neurons, Gastric emptying, gastric hypersensitivity",
author = "Rubina Aktar and Madusha Peiris and Asma Fikree and Simon Eaton and Stamatiki Kritas and Kentish, {Stephen J.} and Araujo, {Eduardo J.A.} and Cristiano Bacarin and Page, {Amanda J.} and Voermans, {Nicol C.} and Qasim Aziz and Blackshaw, {L. Ashley}",
note = "This article is protected by copyright. All rights reserved.",
year = "2019",
month = "1",
day = "3",
doi = "10.1113/JP277195",
language = "English",
journal = "Journal of Physiology",
issn = "0022-3751",
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Aktar, R, Peiris, M, Fikree, A, Eaton, S, Kritas, S, Kentish, SJ, Araujo, EJA, Bacarin, C, Page, AJ, Voermans, NC, Aziz, Q & Blackshaw, LA 2019, 'A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function', Journal of Physiology. https://doi.org/10.1113/JP277195

A novel role for the extracellular matrix glycoprotein-Tenascin-X in gastric function. / Aktar, Rubina; Peiris, Madusha; Fikree, Asma; Eaton, Simon; Kritas, Stamatiki; Kentish, Stephen J.; Araujo, Eduardo J.A.; Bacarin, Cristiano; Page, Amanda J.; Voermans, Nicol C.; Aziz, Qasim; Blackshaw, L. Ashley.

In: Journal of Physiology, 03.01.2019.

Research output: Contribution to journalArticle

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AU - Aktar, Rubina

AU - Peiris, Madusha

AU - Fikree, Asma

AU - Eaton, Simon

AU - Kritas, Stamatiki

AU - Kentish, Stephen J.

AU - Araujo, Eduardo J.A.

AU - Bacarin, Cristiano

AU - Page, Amanda J.

AU - Voermans, Nicol C.

AU - Aziz, Qasim

AU - Blackshaw, L. Ashley

N1 - This article is protected by copyright. All rights reserved.

PY - 2019/1/3

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N2 - KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints to maintain correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalised by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in mouse-model. Our translational studies suggest abnormal gastric sensory function may explain upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities which will enable better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-Baclofen could be beneficial in patients. These hypotheses need confirmation through targeted clinical-trials.ABSTRACT: Tenascin X (TNX) is a glycoprotein that regulates tissue structure through anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers Danlos Syndrome (hEDS) involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal (GI) dysfunction. Previously, we have shown TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We set out to identify if TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice suggesting vagal afferent responses are likely due to altered peripheral mechanosensitivity. In TNXB-deficient patients significantly greater symptoms of reflux, indigestion, and abdominal pain was reported. Here we report the first role for TNX in gastric function and further studies are required in TNX deficient patients to determine if symptoms can be relieved using GABAB agonists. This article is protected by copyright. All rights reserved.

AB - KEY POINTS: Tenascin X (TNX) functions in the extracellular matrix of skin and joints to maintain correct intercellular connections and tissue architecture TNX is associated exclusively with vagal-afferent endings and some myenteric neurones in mouse and human stomach respectively. TNX-deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalised by an inhibitor of vagal-afferent sensitivity. Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX-deficient mice. TNX-deficient patients have upper gastric dysfunction consistent with those in mouse-model. Our translational studies suggest abnormal gastric sensory function may explain upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology. TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities which will enable better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents-Baclofen could be beneficial in patients. These hypotheses need confirmation through targeted clinical-trials.ABSTRACT: Tenascin X (TNX) is a glycoprotein that regulates tissue structure through anti-adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers Danlos Syndrome (hEDS) involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal (GI) dysfunction. Previously, we have shown TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX-deficient patients and mice. We set out to identify if TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report TNX was present in calretinin-immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice suggesting vagal afferent responses are likely due to altered peripheral mechanosensitivity. In TNXB-deficient patients significantly greater symptoms of reflux, indigestion, and abdominal pain was reported. Here we report the first role for TNX in gastric function and further studies are required in TNX deficient patients to determine if symptoms can be relieved using GABAB agonists. This article is protected by copyright. All rights reserved.

KW - enteric neurons

KW - Gastric emptying

KW - gastric hypersensitivity

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