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

Authors: Rasheed, Naslin; Wang, Xueying; Yeh, James; Li, Baojie

Source: Human Molecular Genetics, Volume 15, Number 12, 15 June 2006 , pp. 1938-1948(11)

Publisher: Oxford University Press

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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 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.

Document Type: Research article

DOI: http://dx.doi.org/10.1093/hmg/ddl116

Publication date: 2006-06-15

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