Conditional abrogation of Atm in osteoclasts extends osteoclast lifespan and results in reduced bone mass.
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-κB signaling and an increase in the expression of NF-κB-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.
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.|Japan Society for the Promotion of Science, Tokyo 102-8472, Japan.
Toru
T
Hirozane
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.|Department of Anti-Aging Orthopedic Research, Keio University School of Medicine, Tokyo, Japan.
Takahide
T
Tohmonda
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.|Department of Anti-Aging Orthopedic Research, Keio University School of Medicine, Tokyo, Japan.
Masaki
M
Yoda
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Masayuki
M
Shimoda
Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Yae
Y
Kanai
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Morio
M
Matsumoto
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Hideo
H
Morioka
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.
Masaya
M
Nakamura
Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo 160-8582, Japan.|Department of Anti-Aging Orthopedic Research, Keio University School of Medicine, Tokyo, Japan.
Keisuke
K
Horiuchi
Sci Signal. 2011 Jan 18;4(156):pe2
21245467
Nat Rev Rheumatol. 2011 Apr;7(4):235-43
21386794
Trends Endocrinol Metab. 2012 Nov;23(11):582-90
22705116
J Biol Chem. 2004 Aug 27;279(35):36171-4
15226292
Mol Cell Biol. 2010 Dec;30(24):5787-94
20956556
Mol Cell. 2013 Feb 21;49(4):623-31
23290917
Cell. 2007 Sep 7;130(5):811-23
17803905
Cell Rep. 2015 Nov 24;13(8):1623-32
26586427
Mol Cell Biol. 1999 Jul;19(7):5096-105
10373558
Science. 1998 May 15;280(5366):1089-91
9582124
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16633-8
17921246
Bonekey Rep. 2015 Apr 15;4:665
25908968
Science. 2006 Feb 24;311(5764):1141-6
16497931
J Neurosci. 2003 Sep 17;23(24):8586-95
13679428
N Engl J Med. 1970 Jun 18;282(25):1396-402
4192270
Nat Rev Rheumatol. 2015 Mar;11(3):189-94
25422000
PLoS One. 2012;7(6):e38246
22715377
Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2028-33
21245310
Bone. 2005 Oct;37(4):497-503
16027059
Trends Biochem Sci. 2012 Jan;37(1):15-22
22079189
Hum Mol Genet. 2006 Jun 15;15(12):1938-48
16644862
J Exp Med. 2007 Jul 9;204(7):1613-23
17576777
Annu Rev Pathol. 2012;7:303-21
22035194
Blood. 2012 Feb 9;119(6):1490-500
22144182
Genes Dev. 1996 Oct 1;10(19):2411-22
8843194
Nat Rev Mol Cell Biol. 2013 Apr;14(4):197-210
23847781
J Clin Invest. 2009 Oct;119(10):3149-59
19759519
Cell. 1996 Jul 12;86(1):159-71
8689683
Front Genet. 2013 Mar 25;4:37
23532176
Acta Oncol. 2001;40(6):686-8
11765061
Nature. 2006 Jul 27;442(7101):466-70
16799570
J Cell Physiol. 2009 Aug;220(2):450-9
19365810
Science. 2000 Sep 1;289(5484):1504-8
10968780
Development. 1998 Oct;125(20):4007-17
9735362
Nat Cell Biol. 2000 Dec;2(12):893-8
11146653
Blood. 2015 Nov 12;126(20):2291-301
26400962
Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1676-81
11172010
J Clin Invest. 2005 Dec;115(12):3318-25
16322775
Blood. 2005 Aug 1;106(3):852-9
15817678
EMBO J. 2004 Nov 10;23(22):4451-61
15510216
J Biol Chem. 1998 Apr 10;273(15):8799-805
9535858
J Clin Invest. 2007 Sep;117(9):2723-34
17786248
Nat Rev Mol Cell Biol. 2008 Oct;9(10):759-69
18813293
DNA Repair (Amst). 2016 Mar;39:1-20
26777338
Science. 2013 Feb 8;339(6120):700-4
23306437
J Clin Invest. 2015 Aug 3;125(8):3269-79
26193638
Nat Commun. 2013;4:2062
23797602
J Biol Chem. 2015 Apr 10;290(15):9377-86
25691576