Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice

Abstract Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the...

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Autores principales:	Hilène Lin, Eric Hay, Augustin Latourte, Thomas Funck-Brentano, Wafa Bouaziz, Hang-Korng Ea, Abdel-Majid Khatib, Pascal Richette, Martine Cohen-Solal
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e1fe44008e4a4387b656a1af39f60073
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spelling	oai:doaj.org-article:e1fe44008e4a4387b656a1af39f600732021-12-02T15:08:17ZProprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice10.1038/s41598-018-28713-22045-2322https://doaj.org/article/e1fe44008e4a4387b656a1af39f600732018-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-28713-2https://doaj.org/toc/2045-2322Abstract Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor α1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), α1-PDX (14 µg/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 ± 0.75 vs 9.16 ± 0.6, p < 0.01), and the number of MMP-13(+) chondrocytes was lower (4.96 ± 0.60% vs 20.96 ± 8.49%, p < 0.05). Moreover, furin prevented the increase in ALK1/ALK5 ratio in cartilage induced by OA. Conversely, α1-PDX had no effect on OA cartilage structure. These results support a protective role for furin in OA by maintaining ALK5 receptor levels and reducing MMP-13 expression. Therefore, furin might be a potential target mediating the development of OA.Hilène LinEric HayAugustin LatourteThomas Funck-BrentanoWafa BouazizHang-Korng EaAbdel-Majid KhatibPascal RichetteMartine Cohen-SolalNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-9 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hilène Lin Eric Hay Augustin Latourte Thomas Funck-Brentano Wafa Bouaziz Hang-Korng Ea Abdel-Majid Khatib Pascal Richette Martine Cohen-Solal Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
description	Abstract Cartilage loss in osteoarthritis (OA) results from altered local production of growth factors and metalloproteases (MMPs). Furin, an enzyme involved in the protein maturation of MMPs, might regulate chondrocyte function. Here, we tested the effect of furin on chondrocyte catabolism and the development of OA. In primary chondrocytes, furin reduced the expression of MMP-13, which was reversed by treatment with the furin inhibitor α1-PDX. Furin also promoted the activation of Smad3 signaling, whereas activin receptor-like kinase 5 (ALK5) knockdown mitigated the effects of furin on MMP-13 expression. Mice underwent destabilization of the medial meniscus (DMM) to induce OA, then received furin (1 U/mice), α1-PDX (14 µg/mice) or vehicle. In mice with DMM, the OA score was lower with furin than vehicle treatment (6.42 ± 0.75 vs 9.16 ± 0.6, p < 0.01), and the number of MMP-13(+) chondrocytes was lower (4.96 ± 0.60% vs 20.96 ± 8.49%, p < 0.05). Moreover, furin prevented the increase in ALK1/ALK5 ratio in cartilage induced by OA. Conversely, α1-PDX had no effect on OA cartilage structure. These results support a protective role for furin in OA by maintaining ALK5 receptor levels and reducing MMP-13 expression. Therefore, furin might be a potential target mediating the development of OA.
format	article
author	Hilène Lin Eric Hay Augustin Latourte Thomas Funck-Brentano Wafa Bouaziz Hang-Korng Ea Abdel-Majid Khatib Pascal Richette Martine Cohen-Solal
author_facet	Hilène Lin Eric Hay Augustin Latourte Thomas Funck-Brentano Wafa Bouaziz Hang-Korng Ea Abdel-Majid Khatib Pascal Richette Martine Cohen-Solal
author_sort	Hilène Lin
title	Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
title_short	Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
title_full	Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
title_fullStr	Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
title_full_unstemmed	Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice
title_sort	proprotein convertase furin inhibits matrix metalloproteinase 13 in a tgfβ-dependent manner and limits osteoarthritis in mice
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e1fe44008e4a4387b656a1af39f60073
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Proprotein convertase furin inhibits matrix metalloproteinase 13 in a TGFβ-dependent manner and limits osteoarthritis in mice

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