Related Experiment Video
Updated: May 23, 2026
Skeletal Phenotype Analysis of a Conditional Stat3 Deletion Mouse Model
Published on: July 3, 2020
Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice
Claudia Nicolaije1, Karin E M Diderich, S M Botter
1Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Abstract:
Accumulation of DNA damage caused by oxidative stress is thought to be one of the main contributors of human tissue aging. Trichothiodystrophy (TTD) mice have a mutation in the Ercc2 DNA repair gene, resulting in accumulation of DNA damage and several features of segmental accelerated aging. We used male TTD mice to study the impact of DNA repair on bone metabolism with age. Analysis of bone parameters, measured by micro-computed tomography, displayed an earlier decrease in trabecular and cortical bone as well as a loss of periosteal apposition and a reduction in bone strength in TTD mice with age compared to wild type mice. Ex vivo analysis of bone marrow differentiation potential showed an accelerated reduction in the number of osteogenic and osteoprogenitor cells with unaltered differentiation capacity. Adipocyte differentiation was normal. Early in life, osteoclast number tended to be increased while at 78 weeks it was significantly lower in TTD mice. Our findings reveal the importance of genome stability and proper DNA repair for skeletal homeostasis with age and support the idea that accumulation of damage interferes with normal skeletal maintenance, causing reduction in the number of osteoblast precursors that are required for normal bone remodeling leading to a loss of bone structure and strength.
Insights
DNA repair is crucial for maintaining bone health. Trichothiodystrophy (TTD) mice with DNA repair defects show accelerated bone aging and reduced bone strength due to impaired osteoblast precursor cells.
Area of Science:
- Genetics and Aging
- Skeletal Biology
- DNA Repair Mechanisms
Background:
- Oxidative stress-induced DNA damage contributes to aging.
- Trichothiodystrophy (TTD) mice exhibit DNA repair defects (Ercc2 gene mutation) and accelerated aging.
- Understanding DNA repair's role in skeletal aging is vital.
Purpose of the Study:
- To investigate the impact of DNA repair deficiency on bone metabolism in aging TTD mice.
- To assess age-related changes in bone structure, strength, and cellular differentiation in TTD mice.
Main Methods:
- Utilized male Trichothiodystrophy (TTD) mice and wild-type controls.
- Analyzed bone parameters using micro-computed tomography (micro-CT).
- Performed ex vivo bone marrow differentiation assays for osteogenic and adipogenic potential.
Main Results:
- TTD mice showed earlier decreases in trabecular and cortical bone, reduced periosteal apposition, and lower bone strength with age.
- Osteogenic and osteoprogenitor cell numbers were reduced in TTD mice, while differentiation capacity remained unaltered.
- Osteoclast numbers were transiently increased early in life and significantly decreased in aged TTD mice.
Conclusions:
- Genome stability and DNA repair are essential for maintaining skeletal homeostasis during aging.
- Accumulated DNA damage disrupts normal bone remodeling by reducing osteoblast precursors, leading to bone loss and decreased strength.
- DNA repair deficiency accelerates skeletal aging and compromises bone integrity.
Related Concept Videos
01:29Bone Disorders
Bone deposition is also affected by the levels of sex hormones like estrogen and testosterone that promote osteoblast activity and bone matrix synthesis. When the level of these hormones decreases due to aging, it causes a reduction in bone deposition. As a result, bone resorption by osteoclasts...
01:19The Effect of Aging on Tissues