DECREASED OXIDATIVE STRESS AND GREATER BONE ANABOLISM IN THE AGED, AS COMPARED TO THE YOUNG, MURINE SKELETON BY PARATHYROID HORMONE

• Published in: Aging cell 2010-10, Vol.9 (5), p.851-867
• Main Authors: Jilka, R.L., Almeida, M., Ambrogini, E., Han, L., Roberson, P. K., Weinstein, R.S., Manolagas, S.C.
• Format: Article
• Language: English
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/j.1474-9726.2010.00616.x

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. PTH 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 as 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. PTH 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 (ROS), p66 Shc phosphorylation and expression of the lipoxygenase Alox15; and it increased glutathione and stimulated Wnt signaling in bone of old mice. PTH also antagonized the effects of oxidative stress on p66 Shc phosphorylation, FoxO 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.