Cargando…

Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage

Pathologic calcification of cartilage consists of the formation of basic calcium phosphate (BCP) and/or calcium pyrophosphate dihydrate (CPPD) containing calcium crystals in mature hyaline or articular cartilage and is associated with aging, cartilage injury and likely plays a role in accelerating t...

Descripción completa

Detalles Bibliográficos
Autores principales: Nasi, Sonia, Castelblanco, Mariela, Chobaz, Véronique, Ehirchiou, Driss, So, Alexander, Bernabei, Ilaria, Kusano, Teruo, Nishino, Takeshi, Okamoto, Ken, Busso, Nathalie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900416/
https://www.ncbi.nlm.nih.gov/pubmed/33634117
http://dx.doi.org/10.3389/fcell.2021.612440
_version_ 1783654206259855360
author Nasi, Sonia
Castelblanco, Mariela
Chobaz, Véronique
Ehirchiou, Driss
So, Alexander
Bernabei, Ilaria
Kusano, Teruo
Nishino, Takeshi
Okamoto, Ken
Busso, Nathalie
author_facet Nasi, Sonia
Castelblanco, Mariela
Chobaz, Véronique
Ehirchiou, Driss
So, Alexander
Bernabei, Ilaria
Kusano, Teruo
Nishino, Takeshi
Okamoto, Ken
Busso, Nathalie
author_sort Nasi, Sonia
collection PubMed
description Pathologic calcification of cartilage consists of the formation of basic calcium phosphate (BCP) and/or calcium pyrophosphate dihydrate (CPPD) containing calcium crystals in mature hyaline or articular cartilage and is associated with aging, cartilage injury and likely plays a role in accelerating the pathology of osteoarthritis (OA). The pathways regulating joint calcification, in particular cartilage calcification, are not completely understood, but inflammation and the formation of reactive oxygen species (ROS) are contributory factors. The xanthine oxidase (XO) form of xanthine oxidoreductase (XOR), the key enzyme in xanthine and uric acid metabolism, is a major cellular source of superoxide. We hypothesized that XOR could be implicated in chondrocyte mineralization and cartilage calcification and degradation in OA. We showed both in murine primary chondrocyte and chondrogenic ATDC5 cells, that mineralization was inhibited by two different XOR inhibitors, febuxostat and allopurinol. In addition, XOR inhibition reduced the expression of the pro-mineralizing cytokine interleukin-6 (IL-6). We next generated XOR knock-out chondrocyte cell lines with undetectable XOR expression and XO activity. XOR knock-out chondrocyte cells showed decreased mineralization and reduced alkaline phosphatase (Alp) activity. To assess the precise form of XOR involved, primary chondrocytes of XOR mutant mice expressing either the XDH form (XDH ki) or the XO form (XO ki) were studied. We found that XO ki chondrocytes exhibited increased mineralization compared to XDH ki chondrocytes, and this was associated with enhanced Alp activity, ROS generation and IL-6 secretion. Finally, we found increased XOR expression in damaged vs. undamaged cartilage obtained from OA patients and XOR expression partially co-localized with areas showing pathologic calcification. Altogether, our results suggest that XOR, via its XO form, contribute to chondrocyte mineralization and pathological calcification in OA cartilage.
format Online
Article
Text
id pubmed-7900416
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-79004162021-02-24 Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage Nasi, Sonia Castelblanco, Mariela Chobaz, Véronique Ehirchiou, Driss So, Alexander Bernabei, Ilaria Kusano, Teruo Nishino, Takeshi Okamoto, Ken Busso, Nathalie Front Cell Dev Biol Cell and Developmental Biology Pathologic calcification of cartilage consists of the formation of basic calcium phosphate (BCP) and/or calcium pyrophosphate dihydrate (CPPD) containing calcium crystals in mature hyaline or articular cartilage and is associated with aging, cartilage injury and likely plays a role in accelerating the pathology of osteoarthritis (OA). The pathways regulating joint calcification, in particular cartilage calcification, are not completely understood, but inflammation and the formation of reactive oxygen species (ROS) are contributory factors. The xanthine oxidase (XO) form of xanthine oxidoreductase (XOR), the key enzyme in xanthine and uric acid metabolism, is a major cellular source of superoxide. We hypothesized that XOR could be implicated in chondrocyte mineralization and cartilage calcification and degradation in OA. We showed both in murine primary chondrocyte and chondrogenic ATDC5 cells, that mineralization was inhibited by two different XOR inhibitors, febuxostat and allopurinol. In addition, XOR inhibition reduced the expression of the pro-mineralizing cytokine interleukin-6 (IL-6). We next generated XOR knock-out chondrocyte cell lines with undetectable XOR expression and XO activity. XOR knock-out chondrocyte cells showed decreased mineralization and reduced alkaline phosphatase (Alp) activity. To assess the precise form of XOR involved, primary chondrocytes of XOR mutant mice expressing either the XDH form (XDH ki) or the XO form (XO ki) were studied. We found that XO ki chondrocytes exhibited increased mineralization compared to XDH ki chondrocytes, and this was associated with enhanced Alp activity, ROS generation and IL-6 secretion. Finally, we found increased XOR expression in damaged vs. undamaged cartilage obtained from OA patients and XOR expression partially co-localized with areas showing pathologic calcification. Altogether, our results suggest that XOR, via its XO form, contribute to chondrocyte mineralization and pathological calcification in OA cartilage. Frontiers Media S.A. 2021-02-09 /pmc/articles/PMC7900416/ /pubmed/33634117 http://dx.doi.org/10.3389/fcell.2021.612440 Text en Copyright © 2021 Nasi, Castelblanco, Chobaz, Ehirchiou, So, Bernabei, Kusano, Nishino, Okamoto and Busso. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Nasi, Sonia
Castelblanco, Mariela
Chobaz, Véronique
Ehirchiou, Driss
So, Alexander
Bernabei, Ilaria
Kusano, Teruo
Nishino, Takeshi
Okamoto, Ken
Busso, Nathalie
Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title_full Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title_fullStr Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title_full_unstemmed Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title_short Xanthine Oxidoreductase Is Involved in Chondrocyte Mineralization and Expressed in Osteoarthritic Damaged Cartilage
title_sort xanthine oxidoreductase is involved in chondrocyte mineralization and expressed in osteoarthritic damaged cartilage
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900416/
https://www.ncbi.nlm.nih.gov/pubmed/33634117
http://dx.doi.org/10.3389/fcell.2021.612440
work_keys_str_mv AT nasisonia xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT castelblancomariela xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT chobazveronique xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT ehirchioudriss xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT soalexander xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT bernabeiilaria xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT kusanoteruo xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT nishinotakeshi xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT okamotoken xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage
AT bussonathalie xanthineoxidoreductaseisinvolvedinchondrocytemineralizationandexpressedinosteoarthriticdamagedcartilage