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.
Strait
Karen
K
Department of Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
Li
Yan
Y
Dillehay
Dirck L
DL
Weitzmann
M Neale
MN
D000818:Animals; D001862:Bone Resorption / Q000000981:diagnostic imaging / Q000378:metabolism / Q000517:prevention & control*; D024042:Collagen Type I / Q000097:blood; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D015663:Osteoporosis, Postmenopausal / Q000517:prevention & control; D010052:Ovariectomy; D010455:Peptides / Q000097:blood; D011759:Pyrrolidines / Q000494:pharmacology; D011857:Radiographic Image Interpretation, Computer-Assisted; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D014057:Tomography, X-Ray Computed
D024042:Collagen Type I; D004967:Estrogens; D016328:NF-kappa B; D010455:Peptides; D011759:Pyrrolidines; D013859:Thiocarbamates; C052929:collagen type I trimeric cross-linked peptide; C020972:pyrrolidine dithiocarbamic acid