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Tesi etd-05272010-022235

Tipo di tesi
Tesi di dottorato di ricerca
The role of FoxO transcription factors in skeletal homeostasis in mice
Settore scientifico disciplinare
Corso di studi
tutor Prof. Marcocci, Claudio
Parole chiave
  • osteoporosis
  • FoxO
  • oxidative stress
Data inizio appello
Data di rilascio
Riassunto analitico
Aging is associated with decrease bone mass and increase in reactive oxygen species (ROS) that shorten the lifespan of mature osteoblasts and osteocytes by apoptosis. ROS divert the limited pool of β-catenin available in the cells from Wnt–T-Cell factor (Tcf) to FoxO-mediated transcription. Forkhead box O (FoxO) transcription factors defend against oxidative stress by activating genes involved in free radical scavenging and apoptosis. Based on this and evidence that decreased defense against oxidative stress is responsible, at least in part, for the adverse effects of aging on the murine skeleton, we have genetically manipulated FoxOs in mice and investigated the impact of such manipulation on skeletal homeostasis.
Conditional deletion of FoxO1, 3 and 4 in three 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, over-expression of a FoxO3 transgene in mature osteoblasts decreased oxidative stress and osteoblast apoptosis, and increased osteoblast number, bone formation rate and vertebral bone mass. 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.
However, deletion of FoxOs selectively in committed osteoblast precursors expressing Osterix since development increases Wnt signaling and leads to bone anabolism. Indeed, while defending against oxidative stress FoxOs attenuate Wnt signaling and its potent influence on bone mass. Thus, the β-catenin diversion from Wnts to FoxOs is very important to skeletal aging and leads to the fundamental concept that defense against oxidative stress comes with a price, that in the case of the skeleton is decreased bone mass. Selective inactivation of FoxOs in Osterix positive cells unleashes the restraining effects of FoxOs on Wnt signaling thereby increasing the number of osteoblasts to an extent that overcompensates for the adverse effects of ROS on cell survival and causes bone anabolism. Collectively, these findings suggest that the balance between ROS production and its amplification in osteoblastic cells versus defense against ROS by activated FoxOs transcription programs, are critical for bone homeostasis throughout life. An increase in ROS with advancing age decreases the number of osteoblasts by 1) exhausting adult self-renewing mesenchimal progenitors, 2) restraining the proliferation/differentiation of Osterix expressing committed osteoblast precursors, at least in part by the diversion of β-catenin from Wnt/Tcf to FoxO-mediated transcription and 3) by promoting the apoptosis of post mitotic osteoblasts and osteocytes.
Aging is associated also with decrease osteoclast number. ROS, are required for osteolast generation, function and survival and overexpression of FoxO3 in cells of the osteoclast lineage decreases osteoclastogenesis, increases osteoclast apoptosis and increases bone mass.
These lines of evidence suggest that osteoblasts and osteoclasts handle (or compartimentalize) ROS in fundametally different ways and that FoxOs defense mechanism play very different roles in the two cell types.