TY - JOUR
T1 - FoxO-Mediated Defense against Oxidative Stress in Osteoblasts Is Indispensable for Skeletal Homeostasis in Mice
AU - Ambrogini, Elena
AU - Almeida, Maria
AU - Martin-Millan, Marta
AU - Paik, Ji Hye
AU - DePinho, Ronald A.
AU - Han, Li
AU - Goellner, Joseph
AU - Weinstein, Robert S.
AU - Jilka, Robert L.
AU - O'Brien, Charles A.
AU - Manolagas, Stavros C.
N1 - Funding Information:
This work was supported by the National Institutes of Health (P01 AG13918, R01 AR49794), the Department of Veterans Affairs (Merit Review grants to S.C.M., R.S.W., and R.L.J. and a VA Research Enhancement Award Program), and Tobacco Settlement funds provided by the University of Arkansas for Medical Sciences. E.A. is supported by a PhD fellowship from the University of Pisa, Italy. M.M.-M. is the recipient of an award from Marques de Valdecilla Foundation, Santander, Spain. J.-H.P. is Damon Runyon Fellow (DRG 1900-06). R.A.D. is an American Cancer Society Research Professor and supported by the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science. We thank A. Warren, K. Vyas, A. DeLoose, X. Qiu, W. Webb, C. Wicker III, S. Berryhill, R. Shelton, and T. Chambers for technical assistance.
PY - 2010/2/3
Y1 - 2010/2/3
N2 - 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.
AB - 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.
KW - HUMDISEASE
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U2 - 10.1016/j.cmet.2009.12.009
DO - 10.1016/j.cmet.2009.12.009
M3 - Article
C2 - 20142101
AN - SCOPUS:75149146587
SN - 1550-4131
VL - 11
SP - 136
EP - 146
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -