title: Atm-deficient mice: an osteoporosis model with defective osteoblast differentiation and increased osteoclastogenesis.
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.
authors.affiliation: The Institute of Molecular and Cell Biology Proteos, Republic of Singapore.
authors.forename: Naslin
authors.initials: N
authors.lastname: Rasheed
authors.forename: Xueying
authors.initials: X
authors.lastname: Wang
authors.forename: Qing-Tian
authors.initials: QT
authors.lastname: Niu
authors.forename: James
authors.initials: J
authors.lastname: Yeh
authors.forename: Baojie
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015519:Bone Density; D001846:Bone Development / Q000502:physiology; D001862:Bone Resorption; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010024:Osteoporosis / Q000503:physiopathology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D012739:Gonadal Steroid Hormones; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases