Mechanical allodynia in mice with tenascin-X deficiency associated with Ehlers-Danlos syndrome

Emiko Okuda-Ashitaka,Toshiaki Minami,Shota Yamanishi,Hiroki Kamada,Hiroaki Kakumoto,Satoshi Matsukawa,Ken-Ichi Matsumoto,Yuka Kakuchi,Seiji Ito,Takafumi Yoshidu,Sadahito Uto,Naoya Ogura

doi:10.1038/s41598-020-63499-2

Emiko Okuda-Ashitaka, Toshiaki Minami + Show 10 more

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https://doi.org/10.1038/s41598-020-63499-2

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Abstract

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. TNX-deficient patients complain of chronic joint pain, myalgia, paresthesia, and axonal polyneuropathy. However, the molecular mechanisms by which TNX deficiency complicates pain are unknown. Here, we examined the nociceptive behavioral responses of TNX-deficient mice. Compared with wild-type mice, TNX-deficient mice exhibited mechanical allodynia but not thermal hyperalgesia. TNX deficiency also increased pain sensitivity to chemical stimuli and aggravated early inflammatory pain elicited by formalin. TNX-deficient mice were significantly hypersensitive to transcutaneous sine wave stimuli at frequencies of 250 Hz (Aδ fiber responses) and 2000 Hz (Aβ fiber responses), but not to stimuli at frequency of 5 Hz (C fiber responses). In addition, the phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice. These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn.

Highlights

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising
To confirm the expression of TNX mRNA in the pain transmission pathway from peripheral tissues to the spinal cord, we examined the expression of TNX mRNA in the mouse paw, sciatic nerve, dorsal root ganglion (DRG), and spinal cord by using reverse transcription-polymerase chain reaction (RT-PCR) analysis
To clarify which cells express TNX in the sciatic nerve, we immunohistochemically examined its expression with anti-S100, anti-glial fibrillary acidic protein (GFAP), and anti-peripherin antibodies, markers of myelinating Schwann cells, non-myelinating Schwann cells, and unmyelinated axons, respectively

Summary

Introduction

Tenascin-X (TNX) is a member of the extracellular matrix glycoprotein tenascin family, and TNX deficiency leads to Ehlers-Danlos syndrome, a heritable human disorder characterized mostly by skin hyperextensibility, joint hypermobility, and easy bruising. The phosphorylation levels of extracellular signal-related kinase, an active neuronal marker, and the activity of NADPH-diaphorase, a neuronal nitric oxide activation marker, were enhanced in the spinal dorsal horns of TNX-deficient mice These results suggest that TNX deficiency contributes to the development of mechanical allodynia and hypersensitivity to chemical stimuli, and it induces hypersensitization of myelinated A fibers and activation of the spinal dorsal horn. TNX-deficient EDS patients complain of chronic joint pain and chronic myalgia[3,4,5] Neurological features such as peripheral paresthesia and www.nature.com/scientificreports axonal polyneuropathy are frequently observed in the context of TNX-deficient EDS3,5. TNX deficiency induced hypersensitization of myelinated sensory A fibers and central sensitization of the spinal dorsal horn, which induced mechanical allodynia and chemical hyperalgesia

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