Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass

Toru Hirozane, Takahide Tohmonda, Masaki Yoda, Masayuki Shimoda, Yae Kanai, Morio Matsumoto, Hideo Morioka, Masaya Nakamura, Keisuke Horiuchi

研究成果: Article

1 引用 (Scopus)

抄録

Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-B signaling and an increase in the expression of NF-B-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

元の言語English
記事番号34426
ジャーナルScientific Reports
6
DOI
出版物ステータスPublished - 2016 9 28

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Ataxia Telangiectasia
Osteoclasts
Bone and Bones
DNA Damage
Bone Resorption
Insulin Resistance
Signal Transduction
Oxidative Stress
Homeostasis
Phosphotransferases
Maintenance
Lymphocytes
Apoptosis
Growth

ASJC Scopus subject areas

  • General

これを引用

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title = "Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass",
abstract = "Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-B signaling and an increase in the expression of NF-B-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.",
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AU - Hirozane, Toru

AU - Tohmonda, Takahide

AU - Yoda, Masaki

AU - Shimoda, Masayuki

AU - Kanai, Yae

AU - Matsumoto, Morio

AU - Morioka, Hideo

AU - Nakamura, Masaya

AU - Horiuchi, Keisuke

PY - 2016/9/28

Y1 - 2016/9/28

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AB - Ataxia-telangiectasia mutated (ATM) kinase is a central component involved in the signal transduction of the DNA damage response (DDR) and thus plays a critical role in the maintenance of genomic integrity. Although the primary functions of ATM are associated with the DDR, emerging data suggest that ATM has many additional roles that are not directly related to the DDR, including the regulation of oxidative stress signaling, insulin sensitivity, mitochondrial homeostasis, and lymphocyte development. Patients and mice lacking ATM exhibit growth retardation and lower bone mass; however, the mechanisms underlying the skeletal defects are not fully understood. In the present study, we generated mutant mice in which ATM is specifically inactivated in osteoclasts. The mutant mice did not exhibit apparent developmental defects but showed reduced bone mass due to increased osteoclastic bone resorption. Osteoclasts lacking ATM were more resistant to apoptosis and showed a prolonged lifespan compared to the controls. Notably, the inactivation of ATM in osteoclasts resulted in enhanced NF-B signaling and an increase in the expression of NF-B-targeted genes. The present study reveals a novel function for ATM in regulating bone metabolism by suppressing the lifespan of osteoclasts and osteoclast-mediated bone resorption.

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