title: Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids.
abstract: 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.
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Marta
authors.initials: M
authors.lastname: Martin-Millan
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Stewart
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences and the Central Arkansas Veterans Health Care System, Little Rock, Arkansas 72205.
authors.forename: Paula K
authors.initials: PK
authors.lastname: Roberson
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: A Michael
authors.initials: AM
authors.lastname: Parfitt
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.affiliation: Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, and the. Electronic address: manolagasstavros@uams.edu.
authors.forename: Stavros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: 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
chemical_list: D000728:Androgens; D000975:Antioxidants; D004967:Estrogens; D012739:Gonadal Steroid Hormones