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Human Molecular Genetics Advance Access originally published online on April 27, 2006
Human Molecular Genetics 2006 15(12):1938-1948; 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.

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

Naslin Rasheed1,{dagger}, Xueying Wang1,{dagger}, Qing-Tian Niu2, James Yeh2 and Baojie Li1,*

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

* To whom correspondence should be addressed. Tel: +65 65869679; Fax: +65 67791117; Email: libj{at}imcb.a-star.edu.sg

Received September 15, 2005; Accepted April 26, 2006

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 bone morphogenetic proteins 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.

{dagger}The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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