Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis

Abstract A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a d...

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Autores principales:	Hiroyuki Nakamura, Phoung Vo, Ioannis Kanakis, Ke Liu, George Bou-Gharios
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4a728ce84dc940029fcff4c7290a34f6
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spelling	oai:doaj.org-article:4a728ce84dc940029fcff4c7290a34f62021-12-02T17:52:13ZAggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis10.1038/s41598-020-66233-02045-2322https://doaj.org/article/4a728ce84dc940029fcff4c7290a34f62020-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-66233-0https://doaj.org/toc/2045-2322Abstract A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). However, clinically tested global MMP inhibitors have low efficacy that may be due to their lack of selectivity. We previously demonstrated in vitro that a variant of tissue inhibitor of metalloproteinase-3 ([-1A]TIMP3) inhibits ADAMTSs but not MMPs. In this study, we tested whether the selectivity of [-1A]TIMP3 is beneficial compared with that of the wild-type TIMP3 in preventing or delaying the onset of the degenerative effects in a mouse model of osteoarthritis. We generated transgenic mice that overexpressed TIMP3 or [-1A]TIMP3 driven by a chondrocyte-specific type II collagen promoter. TIMP3 transgenic mice showed compromised bone integrity as opposed to [-1A]TIMP3 mice. After surgically induced joint instability, TIMP3 overexpression proved to be less protective in cartilage destruction than [-1A]TIMP3 at late stages of OA. The selective inhibition of ADAMTSs provides the possibility of modifying TIMP3 to specifically target a class of cartilage-degrading proteinases and to minimize adverse effects on bone and possibly other tissues.Hiroyuki NakamuraPhoung VoIoannis KanakisKe LiuGeorge Bou-GhariosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-9 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hiroyuki Nakamura Phoung Vo Ioannis Kanakis Ke Liu George Bou-Gharios Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
description	Abstract A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs). However, clinically tested global MMP inhibitors have low efficacy that may be due to their lack of selectivity. We previously demonstrated in vitro that a variant of tissue inhibitor of metalloproteinase-3 ([-1A]TIMP3) inhibits ADAMTSs but not MMPs. In this study, we tested whether the selectivity of [-1A]TIMP3 is beneficial compared with that of the wild-type TIMP3 in preventing or delaying the onset of the degenerative effects in a mouse model of osteoarthritis. We generated transgenic mice that overexpressed TIMP3 or [-1A]TIMP3 driven by a chondrocyte-specific type II collagen promoter. TIMP3 transgenic mice showed compromised bone integrity as opposed to [-1A]TIMP3 mice. After surgically induced joint instability, TIMP3 overexpression proved to be less protective in cartilage destruction than [-1A]TIMP3 at late stages of OA. The selective inhibition of ADAMTSs provides the possibility of modifying TIMP3 to specifically target a class of cartilage-degrading proteinases and to minimize adverse effects on bone and possibly other tissues.
format	article
author	Hiroyuki Nakamura Phoung Vo Ioannis Kanakis Ke Liu George Bou-Gharios
author_facet	Hiroyuki Nakamura Phoung Vo Ioannis Kanakis Ke Liu George Bou-Gharios
author_sort	Hiroyuki Nakamura
title	Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
title_short	Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
title_full	Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
title_fullStr	Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
title_full_unstemmed	Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis
title_sort	aggrecanase-selective tissue inhibitor of metalloproteinase-3 (timp3) protects articular cartilage in a surgical mouse model of osteoarthritis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/4a728ce84dc940029fcff4c7290a34f6
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Aggrecanase-selective tissue inhibitor of metalloproteinase-3 (TIMP3) protects articular cartilage in a surgical mouse model of osteoarthritis

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