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The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage
Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typic...
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/PMC8471338/ https://www.ncbi.nlm.nih.gov/pubmed/34573065 http://dx.doi.org/10.3390/antiox10091433 |
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author | Nasi, Sonia Ehirchiou, Driss Bertrand, Jessica Castelblanco, Mariela Mitchell, James Ishii, Isao So, Alexander Busso, Nathalie |
author_facet | Nasi, Sonia Ehirchiou, Driss Bertrand, Jessica Castelblanco, Mariela Mitchell, James Ishii, Isao So, Alexander Busso, Nathalie |
author_sort | Nasi, Sonia |
collection | PubMed |
description | Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typical of osteoarthritis (OA). The PC process is poorly understood and treatments able to target the underlying mechanisms of the disease are lacking. Here we show a crucial role of the gasotransmitter hydrogen sulfide (H(2)S) and, in particular, of the H(2)S-producing enzyme cystathionine γ-lyase (CSE), in regulating PC in cartilage. Cse deficiency (Cse KO mice) exacerbated calcification in both surgically-induced (menisectomy) and spontaneous (aging) murine models of cartilage PC, and augmented PC was closely associated with cartilage degradation (OA). On the contrary, Cse overexpression (Cse tg mice) protected from these features. In vitro, Cse KO chondrocytes showed increased calcification, potentially via enhanced alkaline phosphatase (Alpl) expression and activity and increased IL-6 production. The opposite results were obtained in Cse tg chondrocytes. In cartilage samples from patients with OA, CSE expression inversely correlated with the degree of tissue calcification and disease severity. Increased cartilage degradation in murine and human tissues lacking or expressing low CSE levels may be accounted for by dysregulated catabolism. We found higher levels of matrix-degrading metalloproteases Mmp-3 and -13 in Cse KO chondrocytes, whereas the opposite results were obtained in Cse tg cells. Finally, by high-throughput screening, we identified a novel small molecule CSE positive allosteric modulator (PAM), and demonstrated that it was able to increase cellular H(2)S production, and decrease murine and human chondrocyte calcification and IL-6 secretion. Together, these data implicate impaired CSE-dependent H(2)S production by chondrocytes in the etiology of cartilage PC and worsening of secondary outcomes (OA). In this context, enhancing CSE expression and/or activity in chondrocytes could represent a potential strategy to inhibit PC. |
format | Online Article Text |
id | pubmed-8471338 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-84713382021-09-27 The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage Nasi, Sonia Ehirchiou, Driss Bertrand, Jessica Castelblanco, Mariela Mitchell, James Ishii, Isao So, Alexander Busso, Nathalie Antioxidants (Basel) Article Pathologic calcification (PC) is a painful and disabling condition whereby calcium-containing crystals deposit in tissues that do not physiologically calcify: cartilage, tendons, muscle, vessels and skin. In cartilage, compression and inflammation triggered by PC leads to cartilage degradation typical of osteoarthritis (OA). The PC process is poorly understood and treatments able to target the underlying mechanisms of the disease are lacking. Here we show a crucial role of the gasotransmitter hydrogen sulfide (H(2)S) and, in particular, of the H(2)S-producing enzyme cystathionine γ-lyase (CSE), in regulating PC in cartilage. Cse deficiency (Cse KO mice) exacerbated calcification in both surgically-induced (menisectomy) and spontaneous (aging) murine models of cartilage PC, and augmented PC was closely associated with cartilage degradation (OA). On the contrary, Cse overexpression (Cse tg mice) protected from these features. In vitro, Cse KO chondrocytes showed increased calcification, potentially via enhanced alkaline phosphatase (Alpl) expression and activity and increased IL-6 production. The opposite results were obtained in Cse tg chondrocytes. In cartilage samples from patients with OA, CSE expression inversely correlated with the degree of tissue calcification and disease severity. Increased cartilage degradation in murine and human tissues lacking or expressing low CSE levels may be accounted for by dysregulated catabolism. We found higher levels of matrix-degrading metalloproteases Mmp-3 and -13 in Cse KO chondrocytes, whereas the opposite results were obtained in Cse tg cells. Finally, by high-throughput screening, we identified a novel small molecule CSE positive allosteric modulator (PAM), and demonstrated that it was able to increase cellular H(2)S production, and decrease murine and human chondrocyte calcification and IL-6 secretion. Together, these data implicate impaired CSE-dependent H(2)S production by chondrocytes in the etiology of cartilage PC and worsening of secondary outcomes (OA). In this context, enhancing CSE expression and/or activity in chondrocytes could represent a potential strategy to inhibit PC. MDPI 2021-09-08 /pmc/articles/PMC8471338/ /pubmed/34573065 http://dx.doi.org/10.3390/antiox10091433 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 Nasi, Sonia Ehirchiou, Driss Bertrand, Jessica Castelblanco, Mariela Mitchell, James Ishii, Isao So, Alexander Busso, Nathalie The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title | The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title_full | The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title_fullStr | The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title_full_unstemmed | The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title_short | The Gasotransmitter Hydrogen Sulfide (H(2)S) Prevents Pathologic Calcification (PC) in Cartilage |
title_sort | gasotransmitter hydrogen sulfide (h(2)s) prevents pathologic calcification (pc) in cartilage |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471338/ https://www.ncbi.nlm.nih.gov/pubmed/34573065 http://dx.doi.org/10.3390/antiox10091433 |
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