FoxOs in Osteoclastic Cells

Univ Of Arkansas For Med Scis, Little Rock AR

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Abstract

DESCRIPTION: Reactive oxygen species (ROS) are critical signals for the genesis and lifespan of osteoclasts. The increased remodeling and bone loss that occurs following gonadectomy in mice is associated with increased oxidative stress and is prevented by antioxidants indicating that oxidative stress plays an important role in skeletal homeostasis. However, the increased osteoclastogenesis caused by loss of sex steroids is transient and subsides with time. Indeed, skeletal aging is characterized by a decrease in the number of both osteoblasts and osteoclasts despite being associated with increased oxidative stress in mice. FoxO transcription factors are an important defense mechanism against ROS and gain or loss of FoxO function alters bone mass. In studies leading directly to this application, we found that enforced expression of a FoxO3 transgene in osteoclast progenitors increased osteoclast apoptosis, and decreased osteoclast number as determined in ex vivo cultures. Consistent with this, overexpression of FoxO3 in osteoclast progenitors in mice decreased the levels of bone resorption markers and increased vertebral and femoral cancellous bone mass, indicating that FoxO activation attenuates osteoclastogenesis. The above observations form the foundation of the hypothesis that FoxO activation by ROS are important signals for the generation and fate of osteoclastic cells, and bone resorption. FoxOs prevent oxidative stress by up regulating free radical scavenging enzymes, thereby representing an important homeostatic mechanism for skeletal health. Excessive or prolonged FoxO activation decreases osteoclast numbers and reverses the increase in osteoclastogenesis caused by acute estrogen deficiency. To test this hypothesis mice in which FoxO1, 3, and 4 are conditionally deleted in osteoclast precursors and osteoclasts will be characterized, as well as the consequences of the loss of estrogens in mice overexpressing FoxO3 in the same cell population (Aim 1). In addition, in vitro studies will be performed to establish the consequences of FoxO activation or deletion in osteoclast lifespan and differentiation (Aim 2). Finally, mice overexpressing FoxO3 will be deleted of antioxidant or pro-apoptotic proteins to elucidate in vivo the mechanisms via which FoxO activity in osteoclastic cells alters bone mass (Aim 3). This work should advance knowledge of how oxidative stress via FoxO activation alters bone mass, and provide a better understanding of the mechanisms controlling sex steroid deficiency- or age-related osteoporosis.