Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts-Reference-Cited by-同舟云学术

Dysregulation of extracellular matrix and Lysyl Oxidase in Ehlers-Danlos syndrome type IV skin fibroblasts

Published:2024-01-05 Issue:1 Volume:19 Page:
ISSN:1750-1172
Container-title:Orphanet Journal of Rare Diseases
language:en
Short-container-title:Orphanet J Rare Dis

Author:

Foehr Reece,Anderson Keith,Dombrowski Owen,Foehr Anna,Foehr Erik D.^ORCID

Abstract

Abstract Background Ehlers-Danlos syndrome Type IV (aka Vascular Ehlers Danlos, or vEDS) is a dominantly inherited mutation in the Collagen 3A1 gene (COL3A1). The disease is characterized by tissue friability and age-related susceptibility to arterial aneurysm, dissection and rupture as well as uterine and bowl tears. These clinical manifestations result in major surgical intervention and decreased life expectancy. Understanding how mutations in COL3A1 impact the structure and function of the extracellular matrix (ECM) is important to managing the disease and finding treatments. Results Skin fibroblasts from vEDS subjects heterozygous for the p.G588S pathogenic variant in the COL3A1 gene and a normal individual were cultured and studied. Proteomics analysis identified dozens of upregulated proteins related to extracellular matrix dysregulation that is characteristic of fibrosis. Gene expression libraries from cultured primary fibroblasts were screened for messenger RNA (mRNA) markers of ECM degradation. The proteomics and targeted gene expression array results were largely consistent with dysregulation of the extracellular matrix in vEDS. The data show upregulation of multiple Collagen proteins and genes, other ECM components, and enzymes related to ECM processing and turn-over. vEDS fibroblasts expressed significantly more cross linked C-Telopeptide of Collagen III (CTXIII) than normal fibroblasts, indicative of Collagen III degradation and turn-over. Further, the expression and activity of Lysyl Oxidase (LOX), an enzyme that initiates covalent cross-linking of soluble collagen and elastin into protease resistant fibers, is elevated in vEDS fibroblasts compared to normal fibroblasts. Conclusion Together, these findings suggest dysregulated ECM deposition and processing, reminiscent of a state of fibrosis. Therapeutics that target the dysregulated ECM proteins or help replace damaged tissue may improve clinical outcomes.

Publisher

Springer Science and Business Media LLC

Link

https://link.springer.com/content/pdf/10.1186/s13023-023-03007-7.pdf

Reference22 articles.

1. Germain DP. Ehlers-Danlos syndrome type IV. Orphanet J Rare Dis. 2007;2:32.

2. Baderkhan H, Wanhainen, Stenborg A, Stattin E, Bjorck M. Celiprolol treatment in patients with vascular Ehlers-Danlos Syndrome. Eur J Vasc Endovasc Surg. 2021;61:326–31.

3. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of ehlers–danlos syndrome type IV, the vascular type. N Engl J Med. 2000;342:673–80.

4. Frank M, Albuisson J, Ranque B, Golmard L, Mazzella JM, Bal-Theoleyre L, et al. The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. Eur J Hum Genet. 2015;23:1657–64.

5. Chiarelli N, Ritelli M, Zoppi N, Colombi M. Cellular and molecular mechanisms in the pathogenesis of classical, vascular, and hypermobile ehlers–danlos syndromes. Genes. 2019;10:609.