Ataxia telangiectasia mutated (Atm) knockout mice as a model of osteopenia due to impaired bone formation

Bone. 2005 Oct;37(4):497-503. doi: 10.1016/j.bone.2005.05.012.

Abstract

ATM is a member of the PI-3 kinase protein family, encoded by the gene, ATM, responsible for ataxia telangiectasia (AT). AT is recognized as a genomic instability syndrome, sharing accelerated senescence symptoms in human and mouse. Here, we present evidence that the bone phenotype of Atm knockout (AtmKO) mice is similar to that observed in disuse and/or aging syndromes. A significant decrease in 3-dimensional bone volume fraction (BV/TV) of the fifth lumbar vertebra was observed in AtmKO mice by microCT, compared with heterozygous control mice at 10 weeks of age. Bone histomorphometry revealed that both BFR/BS and Oc.S/BS were significantly decreased in KO mice. To determine the cellular basis of this bone phenotype, we employed in vitro osteoclastogenesis and colony formation assays using bone marrow cells derived from KO and control mice. There was no difference in osteoclast formation in ex vivo cultures. CFU-F was markedly reduced in AtmKO-derived cultures compared with control mice, whereas differentiation of calvaria-derived osteoblasts did not differ between the genotypes. Furthermore, expression levels of IGF1R were significantly decreased, and p38 was aberrantly phosphorylated in marrow stromal cells from AtmKO mice. These results indicate that the pathogenesis of the osteopenic phenotype in AtmKO mice is similar to that of disuse and/or aging syndromes and is caused, at least in part, by a stem cell defect due to lack of IGF signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Blotting, Western
  • Bone Development / genetics*
  • Bone Diseases, Metabolic / genetics*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Disease Models, Animal
  • Enzyme Activation
  • Female
  • Male
  • Mice
  • Mice, Knockout
  • Mutation*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / physiology*
  • Receptor, IGF Type 1 / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / physiology*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cell Cycle Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Receptor, IGF Type 1
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases