title: Decreased oxidative stress and greater bone anabolism in the aged, when compared to the young, murine skeleton with parathyroid hormone administration.
abstract: Because of recent insights into the pathogenesis of age-related bone loss, we investigated whether intermittent parathyroid hormone (PTH) administration antagonizes the molecular mechanisms of the adverse effects of aging on bone. Parathyroid hormone produced a greater increase in vertebral trabecular bone mineral density and bone volume as well as a greater expansion of the endocortical bone surface in the femur of 26- when compared to 6 -month-old female C57BL/6 mice. Moreover, PTH increased trabecular connectivity in vertebrae, and the toughness of both vertebrae and femora in old, but not young, mice. Parathyroid hormone also increased the rate of bone formation and reduced osteoblast apoptosis to a greater extent in the old mice. Most strikingly, PTH reduced reactive oxygen species, p66(Shc) phosphorylation, and expression of the lipoxygenase Alox15, and it increased glutathione and stimulated Wnt signaling in bone of old mice. Parathyroid hormone also antagonized the effects of oxidative stress on p66(Shc) phosphorylation, Forkhead Box O transcriptional activity, osteoblast apoptosis, and Wnt signaling in vitro. In contrast, administration of the antioxidants N-acetyl cysteine or pegylated catalase reduced osteoblast progenitors and attenuated proliferation and Wnt signaling. These results suggest that PTH has a greater bone anabolic efficacy in old age because in addition to its other positive actions on bone formation, it antagonizes the age-associated increase in oxidative stress and its adverse effects on the birth and survival of osteoblasts. On the other hand, ordinary antioxidants cannot restore bone mass in old age because they slow remodeling and attenuate osteoblastogenesis by interfering with Wnt signaling.
authors.affiliation: Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, 72205, USA. rljilka@uams.edu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Jilka
authors.forename: Maria
authors.initials: M
authors.lastname: Almeida
authors.forename: Elena
authors.initials: E
authors.lastname: Ambrogini
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Paula K
authors.initials: PK
authors.lastname: Roberson
authors.forename: Robert S
authors.initials: RS
authors.lastname: Weinstein
authors.forename: Starros C
authors.initials: SC
authors.lastname: Manolagas
mesh_terms: D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009097:Multienzyme Complexes / Q000096:biosynthesis; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000008:administration & dosage* / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D000975:Antioxidants; D009097:Multienzyme Complexes; D010281:Parathyroid Hormone; D017382:Reactive Oxygen Species; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051153:Wnt Proteins; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase