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Human Molecular Genetics Advance Access published online on April 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl116
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© 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received September 15, 2005
Revised April 26, 2006
Accepted April 26, 2006

Article

Atm deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis

Naslin Rasheed 1, Xueying Wang 1, Qing-Tian Niu 2, James Yeh 2, and Baojie Li 1 *

1 The Institute of Molecular and Cell Biology Proteos, 61 Biopolis Drive, Singapore 138673 Republic of Singapore
2 Department of Medicine, Winthrop-University Hospital, Mineola, New York 11501 USA

* To whom correspondence should be addressed.
Baojie Li, E-mail: libj{at}imcb.a-star.edu.sg


  Abstract

Atm is a Ser/Thr kinase involved in DNA damage response and is required for genome integrity and stem cell renewal. Here we report an additional role for Atm in bone remodeling. Atm-/- mice showed reduced bone mass, especially at the trabecular bones, accompanied by a decrease in bone formation rate and defective differentiation of osteoblasts, but normal numbers of osteoprogenitor cells and osteoblasts. Atm might affect osteoblast differentiation by modulating the expression of osterix, a lineage specific transcription factor essential for osteoblast maturation, likely via the BMP pathway. Atm-/- mice also displayed a marked increase in osteoclastogenesis and bone resorption although Atm had no cell-autonomous effect on osteoclast differentiation and resorption. Increased osteoclastogenesis could be caused by a substantial reduction in testosterone and estradiol levels in male and female mice respectively. The steroid hormone deficiency is a result of gonad developmental defects, which led to an increase in serum gonadotrophic hormone FSH via a feedback regulation. Overall, these results indicate that Atm deficiency leads to osteoporosis mainly as a result of hypogonadism-induced bone resorption together with compromised osteoblast differentiation, and that Atm plays a positive role in regulating expression of osteoblast specific transcription factor osterix.


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