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Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?
Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Desp...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621259/ https://www.ncbi.nlm.nih.gov/pubmed/34831458 http://dx.doi.org/10.3390/cells10113236 |
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author | Chiarelli, Nicola Zoppi, Nicoletta Venturini, Marina Capitanio, Daniele Gelfi, Cecilia Ritelli, Marco Colombi, Marina |
author_facet | Chiarelli, Nicola Zoppi, Nicoletta Venturini, Marina Capitanio, Daniele Gelfi, Cecilia Ritelli, Marco Colombi, Marina |
author_sort | Chiarelli, Nicola |
collection | PubMed |
description | Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients’ phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients’ quality of life and alleviate their disabilities. |
format | Online Article Text |
id | pubmed-8621259 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-86212592021-11-27 Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? Chiarelli, Nicola Zoppi, Nicoletta Venturini, Marina Capitanio, Daniele Gelfi, Cecilia Ritelli, Marco Colombi, Marina Cells Article Hypermobile Ehlers-Danlos syndrome (hEDS) is the most frequent type of EDS and is characterized by generalized joint hypermobility and musculoskeletal manifestations which are associated with chronic pain, and mild skin involvement along with the presence of more than a few comorbid conditions. Despite numerous research efforts, no causative gene(s) or validated biomarkers have been identified and insights into the disease-causing mechanisms remain scarce. Variability in the spectrum and severity of symptoms and progression of hEDS patients’ phenotype likely depend on a combination of age, gender, lifestyle, and the probable multitude of genes involved in hEDS. However, considering the clinical overlap with other EDS forms, which lead to abnormalities in extracellular matrix (ECM), it is plausible that the mechanisms underlying hEDS pathogenesis also affect the ECM to a certain extent. Herein, we performed a series of in vitro studies on the secretome of hEDS dermal fibroblasts that revealed a matrix metalloproteinases (MMPs) dysfunction as one of the major disease drivers by causing a detrimental feedback loop of excessive ECM degradation coupled with myofibroblast differentiation. We demonstrated that doxycycline-mediated inhibition of MMPs rescues in hEDS cells a control-like ECM organization and induces a partial reversal of their myofibroblast-like features, thus offering encouraging clues for translational studies confirming MMPs as a potential therapeutic target in hEDS with the expectation to improve patients’ quality of life and alleviate their disabilities. MDPI 2021-11-19 /pmc/articles/PMC8621259/ /pubmed/34831458 http://dx.doi.org/10.3390/cells10113236 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chiarelli, Nicola Zoppi, Nicoletta Venturini, Marina Capitanio, Daniele Gelfi, Cecilia Ritelli, Marco Colombi, Marina Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title | Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title_full | Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title_fullStr | Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title_full_unstemmed | Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title_short | Matrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target? |
title_sort | matrix metalloproteinases inhibition by doxycycline rescues extracellular matrix organization and partly reverts myofibroblast differentiation in hypermobile ehlers-danlos syndrome dermal fibroblasts: a potential therapeutic target? |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8621259/ https://www.ncbi.nlm.nih.gov/pubmed/34831458 http://dx.doi.org/10.3390/cells10113236 |
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