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

Hum Mol Genet. 2006 Jun 15;15(12):1938-48. doi: 10.1093/hmg/ddl116. Epub 2006 Apr 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Bone Density
  • Bone Development / physiology
  • Bone Resorption
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Differentiation
  • DNA Repair
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Disease Models, Animal*
  • Down-Regulation
  • Gonadal Steroid Hormones / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Osteoblasts / physiology*
  • Osteoclasts / cytology
  • Osteoclasts / physiology*
  • Osteoporosis / physiopathology*
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Sp7 Transcription Factor
  • Transcription Factors / genetics
  • Tumor Suppressor Proteins / deficiency
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Gonadal Steroid Hormones
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases