Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis

Abstract Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galac...

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Autores principales:	Yoshifumi Ohashi, Nobunori Takahashi, Kenya Terabe, Saho Tsuchiya, Toshihisa Kojima, Cheryl B. Knudson, Warren Knudson, Shiro Imagama
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/26d7bfdef80d45b389fbf4f5a7d05ae5
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spelling	oai:doaj.org-article:26d7bfdef80d45b389fbf4f5a7d05ae52021-12-02T17:56:56ZMetabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis10.1038/s41598-021-94611-92045-2322https://doaj.org/article/26d7bfdef80d45b389fbf4f5a7d05ae52021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-94611-9https://doaj.org/toc/2045-2322Abstract Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.Yoshifumi OhashiNobunori TakahashiKenya TerabeSaho TsuchiyaToshihisa KojimaCheryl B. KnudsonWarren KnudsonShiro ImagamaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yoshifumi Ohashi Nobunori Takahashi Kenya Terabe Saho Tsuchiya Toshihisa Kojima Cheryl B. Knudson Warren Knudson Shiro Imagama Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
description	Abstract Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.
format	article
author	Yoshifumi Ohashi Nobunori Takahashi Kenya Terabe Saho Tsuchiya Toshihisa Kojima Cheryl B. Knudson Warren Knudson Shiro Imagama
author_facet	Yoshifumi Ohashi Nobunori Takahashi Kenya Terabe Saho Tsuchiya Toshihisa Kojima Cheryl B. Knudson Warren Knudson Shiro Imagama
author_sort	Yoshifumi Ohashi
title	Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
title_short	Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
title_full	Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
title_fullStr	Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
title_full_unstemmed	Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
title_sort	metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/26d7bfdef80d45b389fbf4f5a7d05ae5
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Metabolic reprogramming in chondrocytes to promote mitochondrial respiration reduces downstream features of osteoarthritis

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