What old means to bone

Abstract

The adverse effects of aging of other organs (ovaries at menopause) on the skeleton are well known, but ironically little is known of skeletal aging itself. Evidence indicates that age-related changes, such as oxidative stress, are fundamental mechanisms of the decline of bone mass and strength. Unlike the short-lived osteoclasts and osteoblasts, osteocytes--former osteoblasts entombed in the mineralized matrix--live as long as 50 years, and their death is dependent on skeletal age. Osteocyte death is a major contributor to the decline of bone strength with age, and the likely mechanisms are oxidative stress, autophagy failure and nuclear pore "leakiness". Unraveling these mechanisms should improve understanding of the age-related increase in fractures and suggest novel targets for its prevention.

Figure 1

The osteocyte-canalicular network by scanning electron microscopy. Reliefs of the osteocytes and their canalicular network were obtained following acid-etching of murine bone sections to remove the mineral (Courtesy of Lilian Plotkin and Teresita Bellido, Indiana University, and Lynda Bonewald, University of Missouri-Kansas City School of Dentistry).

Figure 2

Putative mechanisms of decreased osteocyte number by the age-associated increase in oxidative stress (OS). The production of H₂O₂ and several other reactive oxygen species, generated during aerobic metabolism within the mitochondria, increases with advancing age. This increase is amplified by the phosphorylation of p66, which oxidizes reduced cytochrome c (C) released from the electron transfer chain, and opens the permeability transition pore leading to apoptosis. Cells attempt to counteract the adverse consequences of OS by several mechanisms, including an increase in different types of autophagy, stimulated by the activation of transcription factors such as FoxOs and NF-kB. Failure of autophagy with age further contributes to the cell demise. Additionally, with advancing age, long lived post-mitotic cells fail to maintain the nuclear pore diffusion barrier as a result of leakiness caused by the oxidation of nucleoporins, such as Nup-93.