Title | FoxO-mediated defense against oxidative stress in osteoblasts is indispensable for skeletal homeostasis in mice. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Ambrogini E, Almeida M, Martin-Millan M, Paik J-H, DePinho RA, Han L, Goellner J, Weinstein RS, Jilka RL, O'Brien CA, Manolagas SC |
Journal | Cell Metab |
Volume | 11 |
Issue | 2 |
Pagination | 136-46 |
Date Published | 2010 Feb 03 |
ISSN | 1932-7420 |
Keywords | Animals, Apoptosis, Cell Cycle Proteins, Cells, Cultured, Forkhead Box Protein O1, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Deletion, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Osteoblasts, Oxidative Stress, Transgenes, Up-Regulation |
Abstract | Aging increases oxidative stress and osteoblast apoptosis and decreases bone mass, whereas forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Conditional deletion of FoxO1, FoxO3, and FoxO4 in 3-month-old mice resulted in an increase in oxidative stress in bone and osteoblast apoptosis and a decrease in the number of osteoblasts, the rate of bone formation, and bone mass at cancellous and cortical sites. The effect of the deletion on osteoblast apoptosis was cell autonomous and resulted from oxidative stress. Conversely, overexpression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis and increased osteoblast number, bone formation rate, and vertebral bone mass. We conclude that FoxO-dependent oxidative defense provides a mechanism to handle the oxygen free radicals constantly generated by the aerobic metabolism of osteoblasts and is thereby indispensable for bone mass homeostasis. |
DOI | 10.1016/j.cmet.2009.12.009 |
Alternate Journal | Cell Metab |
PubMed ID | 20142101 |
Grant List | P01 AG13918 / AG / NIA NIH HHS / United States R01 AR49794 / AR / NIAMS NIH HHS / United States |
Related Faculty:
Ji-Hye Paik, Ph.D.