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High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II
Osteoarthritis is the most prevalent joint disease worldwide, yet progress in development of effective disease-modifying treatments is slow because of lack of insight into the underlying disease pathways. Therefore, we aimed to identify the causal pathogenic mutation in an early-onset osteoarthritis...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570604/ https://www.ncbi.nlm.nih.gov/pubmed/34739320 http://dx.doi.org/10.1126/sciadv.abg8583 |
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author | van Hoolwerff, Marcella Rodríguez Ruiz, Alejandro Bouma, Marga Suchiman, H. Eka D. Koning, Roman I. Jost, Carolina R. Mulder, Aat A. Freund, Christian Guilak, Farshid Ramos, Yolande F. M. Meulenbelt, Ingrid |
author_facet | van Hoolwerff, Marcella Rodríguez Ruiz, Alejandro Bouma, Marga Suchiman, H. Eka D. Koning, Roman I. Jost, Carolina R. Mulder, Aat A. Freund, Christian Guilak, Farshid Ramos, Yolande F. M. Meulenbelt, Ingrid |
author_sort | van Hoolwerff, Marcella |
collection | PubMed |
description | Osteoarthritis is the most prevalent joint disease worldwide, yet progress in development of effective disease-modifying treatments is slow because of lack of insight into the underlying disease pathways. Therefore, we aimed to identify the causal pathogenic mutation in an early-onset osteoarthritis family, followed by functional studies in human induced pluripotent stem cells (hiPSCs) in an in vitro organoid cartilage model. We demonstrated that the identified causal missense mutation in the gelatin-binding domain of the extracellular matrix protein fibronectin resulted in significant decreased binding capacity to collagen type II. Further analyses of formed hiPSC-derived neo-cartilage tissue highlighted that mutated fibronectin affected chondrogenic capacity and propensity to a procatabolic osteoarthritic state. Together, we demonstrate that binding of fibronectin to collagen type II is crucial for fibronectin downstream gene expression of chondrocytes. We advocate that effective treatment development should focus on restoring or maintaining proper binding between fibronectin and collagen type II. |
format | Online Article Text |
id | pubmed-8570604 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85706042021-11-17 High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II van Hoolwerff, Marcella Rodríguez Ruiz, Alejandro Bouma, Marga Suchiman, H. Eka D. Koning, Roman I. Jost, Carolina R. Mulder, Aat A. Freund, Christian Guilak, Farshid Ramos, Yolande F. M. Meulenbelt, Ingrid Sci Adv Biomedicine and Life Sciences Osteoarthritis is the most prevalent joint disease worldwide, yet progress in development of effective disease-modifying treatments is slow because of lack of insight into the underlying disease pathways. Therefore, we aimed to identify the causal pathogenic mutation in an early-onset osteoarthritis family, followed by functional studies in human induced pluripotent stem cells (hiPSCs) in an in vitro organoid cartilage model. We demonstrated that the identified causal missense mutation in the gelatin-binding domain of the extracellular matrix protein fibronectin resulted in significant decreased binding capacity to collagen type II. Further analyses of formed hiPSC-derived neo-cartilage tissue highlighted that mutated fibronectin affected chondrogenic capacity and propensity to a procatabolic osteoarthritic state. Together, we demonstrate that binding of fibronectin to collagen type II is crucial for fibronectin downstream gene expression of chondrocytes. We advocate that effective treatment development should focus on restoring or maintaining proper binding between fibronectin and collagen type II. American Association for the Advancement of Science 2021-11-05 /pmc/articles/PMC8570604/ /pubmed/34739320 http://dx.doi.org/10.1126/sciadv.abg8583 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences van Hoolwerff, Marcella Rodríguez Ruiz, Alejandro Bouma, Marga Suchiman, H. Eka D. Koning, Roman I. Jost, Carolina R. Mulder, Aat A. Freund, Christian Guilak, Farshid Ramos, Yolande F. M. Meulenbelt, Ingrid High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title | High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title_full | High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title_fullStr | High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title_full_unstemmed | High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title_short | High-impact FN1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type II |
title_sort | high-impact fn1 mutation decreases chondrogenic potential and affects cartilage deposition via decreased binding to collagen type ii |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570604/ https://www.ncbi.nlm.nih.gov/pubmed/34739320 http://dx.doi.org/10.1126/sciadv.abg8583 |
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