Collagen Network Formation in In Vitro Models of Musculocontractural Ehlers-Danlos Syndrome

Ayana Hashimoto; Takuya Hirose; Kohei Hashimoto; Shuji Mizumoto; Yuko Nitahara-Kasahara; Shota Saka; Takahiro Yoshizawa; Takashi Okada; Shuhei Yamada; Tomoki Kosho; Takafumi Watanabe; Shinji Miyata; Yoshihiro Nomura

doi:10.3390/genes14020308

Collagen Network Formation in In Vitro Models of Musculocontractural Ehlers-Danlos Syndrome

Genes (Basel). 2023 Jan 24;14(2):308. doi: 10.3390/genes14020308.

Authors

Affiliations

¹ Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwaicho, Fuchu, Tokyo 183-8509, Japan.
² Laboratory of Veterinary Anatomy, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 069-8501, Hokkaido, Japan.
³ Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, Nagoya 468-8503, Aichi, Japan.
⁴ Division of Molecular and Medical Genetics, Center for Gene and Cell Therapy, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
⁵ Division of Animal Research, Research Center for Advanced Science and Technology, Shinshu University, Matsumoto 390-8621, Nagano, Japan.
⁶ Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan.
⁷ Center for Medical Genetics, Shinshu University Hospital, Matsumoto 390-8621, Nagano, Japan.
⁸ Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto 390-8621, Nagano, Japan.
⁹ Research Center for Supports to Advanced Science, Matsumoto 390-8621, Nagano, Japan.

Abstract

Loss-of-function mutations in carbohydrate sulfotransferase 14 (CHST14) cause musculocontractural Ehlers-Danlos syndrome-CHST14 (mcEDS-CHST14), characterized by multiple congenital malformations and progressive connective tissue fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral and ocular system. The replacement of dermatan sulfate chains on decorin proteoglycan with chondroitin sulfate chains is proposed to lead to the disorganization of collagen networks in the skin. However, the pathogenic mechanisms of mcEDS-CHST14 are not fully understood, partly due to the lack of in vitro models of this disease. In the present study, we established in vitro models of fibroblast-mediated collagen network formation that recapacitate mcEDS-CHST14 pathology. Electron microscopy analysis of mcEDS-CHST14-mimicking collagen gels revealed an impaired fibrillar organization that resulted in weaker mechanical strength of the gels. The addition of decorin isolated from patients with mcEDS-CHST14 and Chst14^-/- mice disturbed the assembly of collagen fibrils in vitro compared to control decorin. Our study may provide useful in vitro models of mcEDS-CHST14 to elucidate the pathomechanism of this disease.

Keywords: Ehlers–Danlos syndrome; carbohydrate sulfotransferase 14; collagen; decorin; dermatan sulfate proteoglycan; fibrillogenesis; mcEDS-CHST14.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Collagen
Decorin
Ehlers-Danlos Syndrome* / genetics
Extracellular Matrix / pathology
Mice
Sulfotransferases* / genetics

Substances

Decorin
Sulfotransferases
Collagen

Grants and funding

This research was funded by the Ministry of Education, Culture, Sports, Science & Technology, Japan [grant number 19H03616 to T.K., and 22K05508 to Y.N.], and was supported in part by Grant-in Aid for Research Center for Pathogenesis of Intractable Diseases from the Research Institute of Meijo University (S.M. and S.Y.).