Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar 15:14:1107787.
doi: 10.3389/fgene.2023.1107787. eCollection 2023.

Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome

Emiko Okuda-Ashitaka  1 , Ken-Ichi Matsumoto  2
Affiliations
Review

Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome

Emiko Okuda-Ashitaka et al. Front Genet. .

Abstract

Tenascin-X (TNX) is an extracellular matrix glycoprotein for which a deficiency results in a recessive form of classical-like Ehlers-Danlos syndrome (clEDS), a heritable connective tissue disorder with hyperextensible skin without atrophic scarring, joint hypermobility, and easy bruising. Notably, patients with clEDS also suffer from not only chronic joint pain and chronic myalgia but also neurological abnormalities such as peripheral paresthesia and axonal polyneuropathy with high frequency. By using TNX-deficient (Tnxb -/-) mice, well-known as a model animal of clEDS, we recently showed that Tnxb -/- mice exhibit hypersensitivity to chemical stimuli and the development of mechanical allodynia due to the hypersensitization of myelinated A-fibers and activation of the spinal dorsal horn. Pain also occurs in other types of EDS. First, we review the underlying molecular mechanisms of pain in EDS, especially that in clEDS. In addition, the roles of TNX as a tumor suppressor protein in cancer progression have been reported. Recent in silico large-scale database analyses have shown that TNX is downregulated in various tumor tissues and that high expression of TNX in tumor cells has a good prognosis. We describe what is so far known about TNX as a tumor suppressor protein. Furthermore, some patients with clEDS show delayed wound healing. Tnxb -/- mice also exhibit impairment of epithelial wound healing in corneas. TNX is also involved in liver fibrosis. We address the molecular mechanism for the induction of COL1A1 by the expression of both a peptide derived from the fibrinogen-related domain of TNX and integrin α11.

Keywords: Ehlers-Danlos syndromes; clEDS; fibrosis; pain; tenascin-X; tumor suppressor.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Clinical features of TNX-related clEDS (A) and clEDS-related phenotypes of Tnxb −/− mice (B). Symptoms in many patients with TNX-related clEDS are shown in (A) (van Dijk et al., 2022). Major clEDS-related phenotypes exhibited in Tnxb −/− mice are shown in (B) (Matsumoto and Aoki, 2020). Complaints associated with pain are highlighted by red letters in (A) and (B).
FIGURE 2
FIGURE 2
Model of pathogenesis for mechanical allodynia in Tnxb −/− mice. Somatosensory information is detected in the primary afferent fibers extending to the skin, which in turn is transmitted to the spinal cord and then to the brain. Unmyelinated C-fibers and lightly myelinated Aδ-fibers conduct noxious and thermal signals, whereas myelinated Aβ-fibers conduct innocuous signals such as touch and pressure (Moehring et al., 2018). Tnxb −/− mice exhibited increased sensitivity to innocuous mechanical stimuli but not thermal stimuli, indicating the induction of mechanical allodynia (Okuda-Ashitaka et al., 2020). Likewise, Tnxb −/− mice showed hypersensitization of myelinated Aδ- and Aβ-fibers but not C-fibers. Furthermore, levels of activated neuron markers, phosphorylation of extracellular signal-related kinase and NADPH-diaphorase activity of neuronal nitric oxide were increased in the spinal dorsal horn of Tnxb −/− mice compared to those in wild-type mice. Thus, TNX deficiency is involved in mechanical allodynia associated with hypersensitization of myelinated Aδ- and Aβ-fibers and central sensitization of the spinal cord.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Aktar R., Peiris M., Fikree A., Cibert-Goton V., Walmsley M., Tough I. R., et al. (2018). The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones. J. Physiol. 596 (17), 4237–4251. 10.1113/jp276300 - DOI - PMC - PubMed
    1. Aktar R., Peiris M., Fikree A., Eaton S., Kritas S., Kentish S. J., et al. (2019). A novel role for the extracellular matrix glycoprotein tenascin-X in gastric function. J. Physiol. 597 (6), 1503–1515. 10.1113/jp277195 - DOI - PMC - PubMed
    1. Alcaraz L. B., Exposito J. Y., Chuvin N., Pommier R. M., Cluzel C., Martel S., et al. (2014). Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-β. J. Cell Biol. 205 (3), 409–428. 10.1083/jcb.201308031 - DOI - PMC - PubMed
    1. Bristow J., Tee M. K., Gitelman S. E., Mellon S. H., Miller W. L. (1993). Tenascin-X: A novel extracellular matrix protein encoded by the human xb gene overlapping P450c21B. J. Cell Biol. 122 (1), 265–278. 10.1083/jcb.122.1.265 - DOI - PMC - PubMed
    1. Burch G. H., Gong Y., Liu W., Dettman R. W., Curry C. J., Smith L., et al. (1997). Tenascin-X deficiency is associated with Ehlers-Danlos syndrome. Nat. Genet. 17 (1), 104–108. 10.1038/ng0997-104 - DOI - PubMed

Grants and funding

This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Number JP17K09045 and Osaka Institute of Technology Research Projects Grants to EO-A and by JSPS KAKENHI Grant Number JP19K08470 and a part of Management Expenses Grants to Shimane University to KM.