A common SNP risk variant MT1-MMP causative for Dupuytren's disease has a specific defect in collagenolytic activity

Author(s):Show less -

Itoh, Yoshifumi ^[1] ; Ng, Michael ^[2] ; Wiberg, Akira ^[2] ; Inoue, Katsuaki ^[3] ; Hirata, Narumi ^{[1, 4]} ; Paiva, Katiucia Batista Silva ^{[5, 1]} ; Ito, Noriko ^[1] ; Dzobo, Kim ^[1] ; Sato, Nanami ^{[1, 6]} ; Gifford, Valentina ^[1] ; Fujita, Yasuyuki ^{[6, 7]} ; Inada, Masaki ^[4] ; Furniss, Dominic ^[2]

Affiliation

^[1] Univ Oxford, Kennedy Inst Rheumatol, NDORMS, Oxford OX3 7FY - England

^[2] Univ Oxford, Botnar Res Ctr, NDORMS, Oxford OX3 7HE - England

^[3] Harwell Sci & Innovat Campus, Diamond Light Source, Didcot, Oxon - England

^[4] Tokyo Univ Agr & Technol, Dept Biotechnol & Life Sci, Tokyo - Japan

^[5] Univ Sao Paulo, Dept Anat, Inst Biomed Sci, Sao Paulo - Brazil

^[6] Hokkaido Univ, Inst Med Genet, Div Mol Oncol, Sapporo, Hokkaido - Japan

^[7] Kyoto Univ, Dept Mol Oncol, Sch Med, Kyoto - Japan

• Document type: Journal article
• Source: MATRIX BIOLOGY; v. 97, p. 20-39, MAR 2021.
• Web of Science Citations: 1

Abstract

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. (AU)

• FAPESP's process: 17/26813-9 - Evaluation of the cell-matrix interaction and its influence on the profile of matrix metalloproteinases secreted by human dental pulp stem cells
• Grantee: Katiúcia Batista da Silva Paiva
• Support Opportunities: Scholarships abroad - Research