Fibrillin-1 G234D mutation in the hybrid1 domain causes tight skin associated with dysregulated elastogenesis and increased collagen cross-linking in mice.

Autor: Hossain AS; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan; Department of Pharmacy, Varendra University, Bangladesh., Clarin MTRDC; School of Integrative and Global Major, University of Tsukuba, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan; National Institute for Material Science, Japan., Kimura K; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan., Biggin G; Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, UK., Taga Y; Nippi Research Institute of Biomatrix, Japan., Uto K; National Institute for Material Science, Japan., Yamagishi A; National Institute of Advanced Industrial Science and Technology, Japan., Motoyama E; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan., Narenmandula; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan., Mizuno K; Nippi Research Institute of Biomatrix, Japan., Nakamura C; National Institute of Advanced Industrial Science and Technology, Japan., Asano K; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan., Ohtsuki S; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Japan., Nakamura T; Department of Pharmacology, Kansai Medical University, Japan., Kanki S; Department of Surgery, Osaka Medical and Pharmaceutical University, Japan., Baldock C; Wellcome Trust Centre for Cell-Matrix Research, Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, UK., Raja E; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan. Electronic address: rajaerna@tara.tsukuba.ac.jp., Yanagisawa H; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Japan. Electronic address: hkyanagisawa@tara.tsukuba.ac.jp.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2024 Nov 28. Date of Electronic Publication: 2024 Nov 28.
DOI: 10.1016/j.matbio.2024.11.006
Abstrakt: Fibrillin-1, an extracellular matrix (ECM) protein encoded by the FBN1 gene, serves as a microfibril scaffold crucial for elastic fiber formation and homeostasis in pliable tissue such as the skin. Aside from causing Marfan syndrome, some mutations in FBN1 result in scleroderma, marked by hardened and thicker skin which limits joint mobility. Here, we describe a tight skin phenotype in the Fbn1 G234D/G234D mice carrying a corresponding variant of FBN1 in the hybrid1 domain that was identified in a patient with familial aortic dissection. Unlike scleroderma, skin thickness and collagen fiber abundance do not change in the Fbn1 G234D/G234D mutant skin. Instead, increased collagen cross-links were observed. In addition, short elastic fibers were sparsely located underneath the panniculus muscle layer, and an abundance of thin, aberrant elastic fibers was increased within the subcutaneous fascia, which may have tightened skin attachment to the underlying skeletal muscle. Structurally, Fbn1 G234D/G234D microfibrils have a disrupted shoulder region that shares similarities with hybrid1 deletion mutant microfibrils. We then demonstrate the consequence of fibrillin-1 G234D mutation on dermal fibroblast functions. Mutant primary fibroblasts produce fewer elastic fibers, exhibit slower migration and increased cell stiffness. Moreover, secretome from mutant fibroblasts are marked by enhanced secretion of ECM, ECM-modifying enzymes, proteoglycans and cytokines, which are pro-tissue repair/fibrogenic. The transcriptome of mutant fibroblasts displays an increased expression of myogenic developmental and immune-related genes. Our study proposes that imbalanced ECM homeostasis due to a fibrillin-1 G234Dmutation impacts fibroblast properties with potential ramifications on skin function.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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