Suppression of NF-kappaB activation blocks osteoclastic bone resorption during estrogen deficiency.

Postmenopausal osteoporosis stems from an imbalance in osteoclastic bone resorption with respect to osteoblastic bone formation, a consequence of estrogen deficiency. The nuclear factor-kappaB (NF-kappaB) signal transduction pathway is critical for osteoclast formation and resorption, and suppression of NF-kappaB activation has been shown to block bone resorption in vitro, and to ameliorate inflammatory bone loss in vivo. The use of NF-kappaB antagonists to blunt the bone loss associated with estrogen deficiency however, has not been previously reported. In this study, we investigated whether pharmacological suppression of NF-kappaB signaling protects mice against ovariectomy (ovx)-induced bone loss. Ovx mice were treated with the potent NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) for 4 weeks and bone mineral density (BMD) and indices of bone structure quantitated by dual-energy X-ray absorptiometry (DXA), and micro-computed tomography (microCT). In vivo indices of bone resorption were quantitated in mouse serum using the biochemical marker C-terminal telopeptide of collagen (CTx). Our data revealed that NF-kappaB suppression significantly prevented ovx-induced bone destruction by preventing the increase in ovx-induced osteoclastic bone resorption. Our data suggest that NF-kappaB inhibitors may represent novel anticatabolic therapeutic agents for the amelioration of postmenopausal bone loss.