ROS-activated signals affecting the genesis and lifespan of osteoblasts and osteoclasts and the counter-regulatory actions of sex steroids. In osteoclast precursors, RANKL-induced activation of RANK stimulates ROS production, which is essential for osteoclastogenesis. In addition, mitochondria biogenesis coupled with activation of the transferrin receptor (TIR1) by the iron-transferrin (Fe-Tf) complex stimulates mitochondria respiration and ROS production, which are also essential for osteoclast activation. Estrogens and androgens, acting via their respective receptors (ERα and AR), attenuate both osteoclastogenesis and survival by stimulating GSH and Trx reductase in an ERK-dependant manner (,,,,). In osteoblastic cells, p66shc is an essential mediator of the effects of oxidative stress on apoptosis, NF-κB activation, and cytokine production. Estrogens and androgens attenuate these effects by suppressing p66shc phosphorylation in an ERK-dependent manner (,).