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...

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Autores principales:	Nicola Chiarelli, Nicoletta Zoppi, Marina Venturini, Daniele Capitanio, Cecilia Gelfi, Marco Ritelli, Marina Colombi
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	doxycycline extracellular matrix hypermobile Ehlers-Danlos syndrome matrix metalloproteinases myofibroblasts secretome Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e39ecb1dab794008b454895f1de81445
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spelling	oai:doaj.org-article:e39ecb1dab794008b454895f1de814452021-11-25T17:13:10ZMatrix Metalloproteinases Inhibition by Doxycycline Rescues Extracellular Matrix Organization and Partly Reverts Myofibroblast Differentiation in Hypermobile Ehlers-Danlos Syndrome Dermal Fibroblasts: A Potential Therapeutic Target?10.3390/cells101132362073-4409https://doaj.org/article/e39ecb1dab794008b454895f1de814452021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3236https://doaj.org/toc/2073-4409Hypermobile 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.Nicola ChiarelliNicoletta ZoppiMarina VenturiniDaniele CapitanioCecilia GelfiMarco RitelliMarina ColombiMDPI AGarticledoxycyclineextracellular matrixhypermobile Ehlers-Danlos syndromematrix metalloproteinasesmyofibroblastssecretomeBiology (General)QH301-705.5ENCells, Vol 10, Iss 3236, p 3236 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	doxycycline extracellular matrix hypermobile Ehlers-Danlos syndrome matrix metalloproteinases myofibroblasts secretome Biology (General) QH301-705.5
spellingShingle	doxycycline extracellular matrix hypermobile Ehlers-Danlos syndrome matrix metalloproteinases myofibroblasts secretome Biology (General) QH301-705.5 Nicola Chiarelli Nicoletta Zoppi Marina Venturini Daniele Capitanio Cecilia Gelfi Marco Ritelli Marina Colombi 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?
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	article
author	Nicola Chiarelli Nicoletta Zoppi Marina Venturini Daniele Capitanio Cecilia Gelfi Marco Ritelli Marina Colombi
author_facet	Nicola Chiarelli Nicoletta Zoppi Marina Venturini Daniele Capitanio Cecilia Gelfi Marco Ritelli Marina Colombi
author_sort	Nicola Chiarelli
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_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_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_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?
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/e39ecb1dab794008b454895f1de81445
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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?

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