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Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo

Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, t...

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Autores principales: Kimura, Atsushi, Hirayama, Akiyoshi, Matsumoto, Tatsuaki, Sato, Yuiko, Kobayashi, Tami, Ikeda, Satsuki, Maruyama, Midori, Kaneko, Mari, Shigeta, Mayo, Ito, Eri, Soma, Tomoya, Miyamoto, Kana, Soga, Tomoyoshi, Tomita, Masaru, Oya, Akihito, Matsumoto, Morio, Nakamura, Masaya, Kanaji, Arihiko, Miyamoto, Takeshi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780519/
https://www.ncbi.nlm.nih.gov/pubmed/35050204
http://dx.doi.org/10.3390/metabo12010082
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author Kimura, Atsushi
Hirayama, Akiyoshi
Matsumoto, Tatsuaki
Sato, Yuiko
Kobayashi, Tami
Ikeda, Satsuki
Maruyama, Midori
Kaneko, Mari
Shigeta, Mayo
Ito, Eri
Soma, Tomoya
Miyamoto, Kana
Soga, Tomoyoshi
Tomita, Masaru
Oya, Akihito
Matsumoto, Morio
Nakamura, Masaya
Kanaji, Arihiko
Miyamoto, Takeshi
author_facet Kimura, Atsushi
Hirayama, Akiyoshi
Matsumoto, Tatsuaki
Sato, Yuiko
Kobayashi, Tami
Ikeda, Satsuki
Maruyama, Midori
Kaneko, Mari
Shigeta, Mayo
Ito, Eri
Soma, Tomoya
Miyamoto, Kana
Soga, Tomoyoshi
Tomita, Masaru
Oya, Akihito
Matsumoto, Morio
Nakamura, Masaya
Kanaji, Arihiko
Miyamoto, Takeshi
author_sort Kimura, Atsushi
collection PubMed
description Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo.
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spelling pubmed-87805192022-01-22 Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo Kimura, Atsushi Hirayama, Akiyoshi Matsumoto, Tatsuaki Sato, Yuiko Kobayashi, Tami Ikeda, Satsuki Maruyama, Midori Kaneko, Mari Shigeta, Mayo Ito, Eri Soma, Tomoya Miyamoto, Kana Soga, Tomoyoshi Tomita, Masaru Oya, Akihito Matsumoto, Morio Nakamura, Masaya Kanaji, Arihiko Miyamoto, Takeshi Metabolites Article Ossification of the posterior longitudinal ligament (OPLL), a disease characterized by the ectopic ossification of a spinal ligament, promotes neurological disorders associated with spinal canal stenosis. While blocking ectopic ossification is mandatory to prevent OPLL development and progression, the mechanisms underlying the condition remain unknown. Here we show that expression of hydroxyacid oxidase 1 (Hao1), a gene identified in a previous genome-wide association study (GWAS) as an OPLL-associated candidate gene, specifically and significantly decreased in fibroblasts during osteoblast differentiation. We then newly established Hao1-deficient mice by generating Hao1-flox mice and crossing them with CAG-Cre mice to yield global Hao1-knockout (CAG-Cre/Hao1flox/flox; Hao1 KO) animals. Hao1 KO mice were born normally and exhibited no obvious phenotypes, including growth retardation. Moreover, Hao1 KO mice did not exhibit ectopic ossification or calcification. However, urinary levels of some metabolites of the tricarboxylic acid (TCA) cycle were significantly lower in Hao1 KO compared to control mice based on comprehensive metabolomic analysis. Our data indicate that Hao1 loss does not promote ectopic ossification, but rather that Hao1 functions to regulate the TCA cycle in vivo. MDPI 2022-01-15 /pmc/articles/PMC8780519/ /pubmed/35050204 http://dx.doi.org/10.3390/metabo12010082 Text en © 2022 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
Kimura, Atsushi
Hirayama, Akiyoshi
Matsumoto, Tatsuaki
Sato, Yuiko
Kobayashi, Tami
Ikeda, Satsuki
Maruyama, Midori
Kaneko, Mari
Shigeta, Mayo
Ito, Eri
Soma, Tomoya
Miyamoto, Kana
Soga, Tomoyoshi
Tomita, Masaru
Oya, Akihito
Matsumoto, Morio
Nakamura, Masaya
Kanaji, Arihiko
Miyamoto, Takeshi
Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title_full Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title_fullStr Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title_full_unstemmed Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title_short Hao1 Is Not a Pathogenic Factor for Ectopic Ossifications but Functions to Regulate the TCA Cycle In Vivo
title_sort hao1 is not a pathogenic factor for ectopic ossifications but functions to regulate the tca cycle in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8780519/
https://www.ncbi.nlm.nih.gov/pubmed/35050204
http://dx.doi.org/10.3390/metabo12010082
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