FoxO-Mediated Defense against Oxidative Stress in Osteloblasts, Is Indispensable for Skeletal Homeostasis in Mice

被引：248

作者：

Ambrogini, Elena ^{[1
,2
]}

Almeida, Maria ^{[1
,2
]}

Martin-Milian, Marta ^{[1
,2
]}

Paik, Ji-Hye ^{[3
,4
,5
,6
]}

DePinho, Ronald A. ^{[3
,4
,5
,6
]}

Han, Li ^{[1
,2
]}

Goellner, Joseph ^{[1
,2
]}

Weinstein, Robert S. ^{[1
,2
]}

Jilka, Robert L. ^{[1
,2
]}

O'Brien, Charles A. ^{[1
,2
]}

Manolagas, Stavros C. ^{[1
,2
]}

机构：

[1] Univ Arkansas Med Sci, Ctr Osteoporosis & Metab Bone Dis, Div Endocrinol & Metab, Little Rock, AR 72205 USA

[2] Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA

[3] Harvard Univ, Sch Med, Belfer Inst Appl Canc Sci, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA

[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA

来源：

CELL METABOLISM | 2010年 / 11卷 / 02期

基金：

美国国家卫生研究院;

关键词：

TRANSCRIPTION FACTOR AFX; FORKHEAD-BOX-O; T-CELL-FACTOR; BETA-CATENIN; LIFE-SPAN; BONE LOSS; OSTEOCLAST APOPTOSIS; CRUCIAL ROLE; FAS LIGAND; IN-VIVO;

D O I：

10.1016/j.cmet.2009.12.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：136 / 146

页数：11

共 66 条

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Motif module map reveals enforcement of aging by continual NF-κB activity [J].