Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice

PLoS One. 2012;7(4):e35246. doi: 10.1371/journal.pone.0035246. Epub 2012 Apr 10.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipocytes / physiology
  • Age Factors
  • Animals
  • Bone Remodeling / genetics
  • Bone Remodeling / physiology
  • Bone and Bones / metabolism*
  • Bone and Bones / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • DNA Repair*
  • Gene Expression / genetics
  • Hematopoietic Stem Cells / metabolism
  • Hematopoietic Stem Cells / physiology
  • Homeostasis / genetics
  • Homeostasis / physiology
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / physiology
  • Mice
  • Mice, Inbred C57BL
  • Osteoblasts / metabolism
  • Osteoblasts / physiology
  • Osteoclasts / metabolism
  • Osteoclasts / physiology
  • Osteogenesis / genetics
  • Osteogenesis / physiology
  • Trichothiodystrophy Syndromes / genetics*
  • Trichothiodystrophy Syndromes / metabolism*