Skeletal Involution by Age-associated Oxidative Stress and Its Acceleration by Loss of Sex Steroids*

By Maria Almeida, Li Han, M. Martín-Millán, L. Plotkin, S. Stewart, P. Roberson, S. Kousteni, Charles A. O’Brien, T. Bellido, A. Parfitt and 3 more. Journal of Biological Chemistry, 2007

669 citations recorded by the source corpus.

Both aging and loss of sex steroids have adverse effects on skeletal homeostasis, but whether and how they may influence each others negative impact on bone remains unknown. We report herein that both female and male C57BL/6 mice progressively lost strength (as determined by load-to-failure measurements) and bone mineral density in the spine and femur between the ages of 4 and 31 months. These changes were temporally associated with decreased rate of remodeling as evidenced by decreased osteoblast and osteoclast numbers and decreased bone formation rate; as well as increased osteoblast and osteocyte apoptosis, increased reactive oxygen species levels, and decreased glutathione reductase activity and a corresponding increase in the phosphorylation of p53 and p66shc, two key components of a signaling cascade that are activated by reactive oxygen species and influences apoptosis and lifespan. Exactly the same changes in oxidative stress were acutely reproduced by gonadectomy in 5-month-old females or males and reversed by estrogens or androgens in vivo as well as in vitro.We conclude that the oxidative stress that underlies physiologic organismal aging in mice may be a pivotal pathogenetic mechanism of the age-related bone loss and strength. Loss of estrogens or androgens accelerates the effects of aging on bone by decreasing defense against oxidative stress.

Subfields: Molecular Biology, Orthopedics and Sports Medicine, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/c7c4a22133a8a6b7ead8b5b4fe0fcfff54d858c9

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In Molecular Biology

1. S. Khosla
2. S. Manolagas
3. D. Monroe
4. M. Oursler
5. R. Jilka
6. L. Bonewald

In Orthopedics and Sports Medicine

1. S. Manolagas
2. S. Khosla
3. D. Monroe
4. M. Oursler

Citations in the corpus

• Estrogen and the Skeleton (2012, positive): “Interestingly, the effects of aging on oxidative stress are recapitulated by the loss of estrogen; moreover, effects of estrogen deficiency on bone are reversed by antioxidants (51).”
• Oxidative stress in bone remodeling: role of antioxidants. (2017, background): “ROS induce the apoptosis of osteoblasts and osteocytes, cells localized in the bone matrix and derived from mature osteoblasts, thus favouring osteoclastogenesis (19, 30, 31, 41, 42) (Figure 1).”
• From estrogen-centric to aging and oxidative stress: a revised perspective of the pathogenesis of osteoporosis. (2010, background): “Furthermore, in vitro NAC prevents osteoclast formation and NF- B activation, whereas BSO and H2O2 have the opposite effect, consistent with the evidence that a certain level of ROS generation is essential for osteoclast generation.”