Lifelong accumulation of bone in mice lacking Pten in osteoblasts.
Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan and activity are regulated by growth factor signaling networks. Growth factors activate phosphatidylinositol 3-kinase (PI3K), which enhances cell survival and antagonizes apoptosis through activation of Akt/PKB. This process is negatively regulated by the Pten phosphatase, which inhibits the activity of PI3K. In this study, we investigated the effects of Akt activation in bone in vivo by conditionally disrupting the Pten gene in osteoblasts by using Cre-mediated recombination. Mice deficient in Pten in osteoblasts were of normal size but demonstrated a dramatic and progressively increasing bone mineral density throughout life. In vitro osteoblasts lacking Pten differentiated more rapidly than controls and exhibited greatly reduced apoptosis in association with markedly increased levels of phosphorylated Akt and activation of signaling pathways downstream of activated Akt. These findings support a critical role for this tumor-suppressor gene in regulating osteoblast lifespan and likely explain the skeletal abnormalities in patients carrying germ-line mutations of PTEN.
Liu
Ximeng
X
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Bruxvoort
Katia J
KJ
Zylstra
Cassandra R
CR
Liu
Jiarong
J
Cichowski
Rachel
R
Faugere
Marie-Claude
MC
Bouxsein
Mary L
ML
Wan
Chao
C
Williams
Bart O
BO
Clemens
Thomas L
TL
D000818:Animals; D017209:Apoptosis; D049628:Body Size; D015519:Bone Density; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology*; D010012:Osteogenesis / Q000502:physiology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency* / Q000502:physiology*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction
D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse