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
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
Publication date: 2006-06-15
- Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics.