期刊
MATRIX BIOLOGY
卷 97, 期 -, 页码 20-39出版社
ELSEVIER
DOI: 10.1016/j.matbio.2021.02.003
关键词
Dupuytren's disease; SNP; rs1042704; MT1-MMP; Collagen degradation
资金
- Kennedy Trust of Rheumatology Research Studentship
- Intermediate Clinical Fellowship from the Wellcome Trust [097152/Z/11/Z]
- NIHR Biomedical Research Centre, Oxford
- Medical Research council [MR/N013468/1]
- Japan Society for Promotion of Science Overseas Challenge Program for Young Researchers
- Sao Paulo Research Foundation [2017/26813-9]
- [17H02157]
- Wellcome Trust [097152/Z/11/Z] Funding Source: Wellcome Trust
The variant rs1042704 in the MMP14 gene was found to significantly reduce collagen catabolism in Dupuytren's Disease, leading to a fibrotic phenotype. This variant alters cell surface collagenolytic activity and acts in a dominant negative manner, affecting the balance of collagen homeostasis in tissue.
Dupuytren's Disease (DD) is a common fibroproliferative disease of the palmar fascia. We previously identified a causal association with a non-synonymous variant (rs1042704, p.D273N) in MMP14 (encoding MT1-MMP). In this study, we investigated the functional consequences of this variant, and demonstrated that the variant MT1-MMP (MT1-N-273) exhibits only 17% of cell surface collagenolytic activity compared to the ancestral enzyme (MT1-D-273). Cells expressing both MT1-D-273 and MT1-N-273 in a 1:1 ratio, mimicking the heterozygous state, possess 38% of the collagenolytic activity compared to the cells expressing MT1-D-273, suggesting that MT1-N-273 acts in a dominant negative manner. Consistent with the above observation, patient-derived DD myofibroblasts with the alternate allele demonstrated around 30% of full collagenolytic activity detected in ancestral G/G genotype cells, regardless of the heterozygous (G/A) or homozygous (A/A) state. Small angle X-ray scattering analysis of purified soluble Fc-fusion enzymes allowed us to construct a 3D-molecular envelope of MT1-D-273 and MT1-N-273, and demonstrate altered flexibility and conformation of the ectodomains due to D273 to N substitution. Taking together, rs1042704 significantly reduces collagen catabolism in tissue, which tips the balance of homeostasis of collagen in tissue, contributing to the fibrotic phenotype of DD. Since around 30% of the worldwide population have at least one copy of the low collagenolytic alternate allele, further investigation of rs1042704 across multiple pathologies is needed. (C) 2021 Elsevier B.V. All rights reserved.
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