Reactive oxygen species induce the association of SHP-1 with c-Src and the oxidation of both to enhance osteoclast survival.

Loss of ovarian function causes oxidative stress as well as bone loss. We hypothesized that reactive oxygen species (ROS) induced by the failure of ovarian function are responsible for the bone loss by increasing the number of osteoclasts (OC). We found that ROS enhanced OC survival via Src homology 2 domain-containing phosphatase-1 (SHP-1), c-Src, Akt, and ERK. ROS induced the association of SHP-1 with c-Src as well as the oxidation of c-Src and SHP-1. This resulted in inactivation of SHP-1 and activation of c-Src via phosphorylation of Tyr(416). Knockdown of c-Src or SHP-1 abolished the effect of ROS on OC survival. Moreover, downregulation of SHP-1 upregulated activation of c-Src, Akt, and ERK in the absence of any stimulus, suggesting that inactivation of SHP-1 is required for OC survival. We demonstrated that the association and oxidation of c-Src and SHP-1 by ROS are key steps in enhancing OC survival, which are responsible for increased bone loss when ovarian function ceases.