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.
Highlights
Osteoporosis, caused by a natural loss of estrogens, has been the main focus of the bone field for many years
The endocortical volume (Ec.V.), known as the total volume contained by the endosteal surface of the cortical bone, was significantly lower in 13 weeks old TTD mice compared to wild type mice of the same age
Trabecular number (Tb.N.) which decreased in wild types throughout life, is significantly lower in TTD mice, with the biggest difference observed at 13 weeks when TTD mice have about half the number of trabecules found in wild type mice of the same age (Fig. 1C)
Summary
Osteoporosis, caused by a natural loss of estrogens, has been the main focus of the bone field for many years. Recently a growing body of evidence supports a more general, age-related form of bone loss, which occurs independent of changes in sex steroid hormone levels and starts at an early age [1]. Early onset and gradual bone loss has been found in several mouse strains independent of a sudden loss of estrogens starting 2–3 months after birth [4,5]. This age-related bone loss is characterised by a slower, more gradual decline in bone mass than in case of post menopausal bone loss [6]. Oxidative stress is induced by reactive oxygen species (ROS) formed as by-products of mitochondrial aerobic metabolism and fatty acid oxidation [7]
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