Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.
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Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice. / Nicolaije, Claudia; Diderich, Karin E M; Botter, S M; Priemel, Matthias; Waarsing, Jan H; Day, Judd S; Brandt, Renata M C; Schilling, Arndt F; Weinans, Harrie; Eerden, Van der; Bram, C; Horst, van der; Gijsbertus, T J; Hoeijmakers, Jan H J; Leeuwen, van; Johannes, P T M.
In: PLOS ONE, Vol. 7, No. 4, 4, 2012, p. 35246.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Age-related skeletal dynamics and decrease in bone strength in DNA repair deficient male trichothiodystrophy mice.
AU - Nicolaije, Claudia
AU - Diderich, Karin E M
AU - Botter, S M
AU - Priemel, Matthias
AU - Waarsing, Jan H
AU - Day, Judd S
AU - Brandt, Renata M C
AU - Schilling, Arndt F
AU - Weinans, Harrie
AU - Eerden, Van der
AU - Bram, C
AU - Horst, van der
AU - Gijsbertus, T J
AU - Hoeijmakers, Jan H J
AU - Leeuwen, van
AU - Johannes, P T M
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Animals
KW - Male
KW - Age Factors
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression/genetics
KW - Cell Differentiation/genetics/physiology
KW - Osteoblasts/metabolism/physiology
KW - DNA Repair
KW - Adipocytes/metabolism/physiology
KW - Bone Remodeling/genetics/physiology
KW - Bone and Bones/metabolism/physiology
KW - Hematopoietic Stem Cells/metabolism/physiology
KW - Homeostasis/genetics/physiology
KW - Mesenchymal Stromal Cells/metabolism/physiology
KW - Osteoclasts/metabolism/physiology
KW - Osteogenesis/genetics/physiology
KW - Trichothiodystrophy Syndromes/genetics/metabolism
KW - Animals
KW - Male
KW - Age Factors
KW - Mice
KW - Mice, Inbred C57BL
KW - Gene Expression/genetics
KW - Cell Differentiation/genetics/physiology
KW - Osteoblasts/metabolism/physiology
KW - DNA Repair
KW - Adipocytes/metabolism/physiology
KW - Bone Remodeling/genetics/physiology
KW - Bone and Bones/metabolism/physiology
KW - Hematopoietic Stem Cells/metabolism/physiology
KW - Homeostasis/genetics/physiology
KW - Mesenchymal Stromal Cells/metabolism/physiology
KW - Osteoclasts/metabolism/physiology
KW - Osteogenesis/genetics/physiology
KW - Trichothiodystrophy Syndromes/genetics/metabolism
U2 - 10.1371/journal.pone.0035246
DO - 10.1371/journal.pone.0035246
M3 - SCORING: Journal article
VL - 7
SP - 35246
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 4
M1 - 4
ER -
