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Lookup NU author(s): Helen Dietmar, Dr Ella DennisORCiD, Dr Francesca Johnson de Sousa Brito, Dr Louise ReynardORCiD, Professor David YoungORCiD, Professor Michael BriggsORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2025 by the authors.The intracellular retention of misfolded extracellular matrix proteins is a common disease mechanism in various rare skeletal diseases. This discovery has driven the study of ER stress and the unfolded protein response (UPR) as a promising therapeutic target in several skeletal dysplasias. In the case of COL10A1 mutations, targeting the UPR resulted in a clinical trial of the repurposed drug carbamazepine; however, for other closely related skeletal disorders, treatment with carbamazepine was ineffective, indicating the need for suitable markers for in vitro screenings of potential drug treatments. Mutations in cartilage oligomeric matrix protein (COMP), a cartilage structural protein, cause both multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH); together referred to as the COMPopathies, which result from the intracellular retention of mutant COMP to varying degrees. In contrast to other closely related skeletal disorders, caused by mutations in cartilage structural proteins, the involvement of the UPR is less clear, and so far, no common COMPopathy marker has been identified. Here, using cell models of COMPopathies, we identified MMP9 upregulation as a common feature of six pathogenic COMP variants that do not induce a prominent UPR. We further show that the archetypal p.V194D matrilin-3 MED variant (which causes MED) does not induce MMP9 expression, suggesting that MMP9 upregulation could serve as a specific marker of COMPopathies in vitro.
Author(s): Dietmar HF, Dennis EP, Johnson de Sousa Brito FM, Reynard LN, Young DA, Briggs MD
Publication type: Article
Publication status: Published
Journal: International Journal of Molecular Sciences
Year: 2025
Volume: 26
Issue: 24
Online publication date: 15/12/2025
Acceptance date: 03/12/2025
Date deposited: 05/01/2026
ISSN (print): 1661-6596
ISSN (electronic): 1422-0067
Publisher: MDPI
URL: https://doi.org/10.3390/ijms262412070
DOI: 10.3390/ijms262412070
Data Access Statement: Additional data are available from the corresponding author upon reasonable request
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