Related Experiment Video
Updated: Aug 16, 2026
Using Inducible Osteoblastic Lineage-Specific Stat3 Knockout Mice to Study Alveolar Bone Remodeling During Orthodontic Tooth Movement
Published on: July 21, 2023
Ataxia telangiectasia mutated (Atm) knockout mice as a model of osteopenia due to impaired bone formation
Akinori Hishiya1, Masako Ito, Hiroyuki Aburatani
1Department of Bone and Joint Disease, National Institute for Longevity Sciences (NILS), National Center for Geriatrics and Gerontology (NCGG), 36-3 Gengo, Morioka-cho, Obu, Aichi 474-8522, Japan.
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.
Insights
Ataxia telangiectasia (AT) gene mutations in mice lead to reduced bone density, mimicking aging and disuse syndromes. This bone loss stems from stem cell defects and impaired insulin-like growth factor signaling.
Area of Science:
- Genetics
- Bone Biology
- Cellular Biology
Background:
- Ataxia telangiectasia (AT) is a genomic instability syndrome.
- ATM gene mutations are linked to AT and accelerated senescence.
- The bone phenotype in Atm knockout (AtmKO) mice is not well understood.
Purpose of the Study:
- To investigate the bone phenotype in AtmKO mice.
- To determine the cellular mechanisms underlying bone loss in AtmKO mice.
- To compare the AtmKO bone phenotype to disuse and aging syndromes.
Main Methods:
- Microcomputed tomography (microCT) for bone volume analysis.
- Bone histomorphometry to assess bone formation and resorption.
- In vitro osteoclastogenesis and colony formation assays.
- Analysis of IGF1R and p38 signaling pathways.
Main Results:
- AtmKO mice exhibited significantly reduced bone volume fraction (BV/TV) in the lumbar vertebra.
- Bone formation rates (BFR/BS) and osteoclast surface (Oc.S/BS) were decreased in AtmKO mice.
- Reduced colony-forming unit-fibroblast (CFU-F) in AtmKO bone marrow cells indicated a stem cell defect.
- Decreased IGF1R expression and aberrant p38 phosphorylation were observed in AtmKO marrow stromal cells.
Conclusions:
- The osteopenic phenotype in AtmKO mice resembles disuse and aging-related bone loss.
- Bone loss is partly due to a stem cell defect caused by impaired IGF signaling.
- ATM deficiency impacts bone health through effects on mesenchymal stem cells and growth factor signaling.
