Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids.
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 p66(shc), 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.
Almeida
Maria
M
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Han
Li
L
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Martin-Millan
Marta
M
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Plotkin
Lilian I
LI
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Stewart
Scott A
SA
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Roberson
Paula K
PK
Department of Biostatistics, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205.
Kousteni
Stavroula
S
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
O'Brien
Charles A
CA
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Bellido
Teresita
T
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Parfitt
A Michael
AM
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Weinstein
Robert S
RS
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Jilka
Robert L
RL
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
Manolagas
Stavros C
SC
Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the. Electronic address: manolagasstavros@uams.edu.
D000375:Aging / Q000502:physiology*; D000728:Androgens / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015519:Bone Density; D016723:Bone Remodeling; D001842:Bone and Bones / Q000502:physiology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis; D010052:Ovariectomy; D018384:Oxidative Stress; D010766:Phosphorylation
D000728:Androgens; D000975:Antioxidants; D004967:Estrogens; D012739:Gonadal Steroid Hormones