Suppression of NF-κB Increases Bone Formation and Ameliorates Osteopenia in Ovariectomized Mice

Bone degenerative diseases, including osteoporosis, impair the fine balance between osteoclast bone resorption and osteoblast bone formation. Single-agent therapy for anabolic and anticatabolic effects is attractive as a drug target to ameliorate such conditions. Inhibition of nuclear factor (NF)-kappa B reduces the osteoclast bone resorption. The role of NF-kappa B inhibitors on osteoblasts and bone formation, however, is minimal and not well investigated. Using an established NF-kappa B inhibitor named S1627, we demonstrated that inhibition of NF-kappa B increases osteoblast differentiation and bone formation in vitro by up-regulating the mRNAs of osteoblast-specific genes like type I collagen, alkaline phosphatase, and osteopontin. In addition, S1627 was able to increase bone formation and repair bone defect in a murine calvarial defect model. To determine the effect of NF-kappa B on a model of osteoporosis, we injected two doses of inhibitor (25 and 50 mg/kg.d) twice a day in sham-operated or ovariectomized 12-wk-old mice and killed them after 4 wk. The anabolic effect of S1627 on trabecular bone was determined by micro focal computed tomography and histomorphometry. Bone mineral density of inhibitor-treated ovariectomized animals was significantly increased compared with sham-operated mice. Osteoblast-related indices like osteoblast surface, mineral apposition rate, and bone formation rate were increased in S1627-treated animals in a dose-dependent manner. NF-kappa B inhibition by S1627 increased the trabecular bone volume in ovariectomized mice. Furthermore, S1627 could inhibit the osteoclast number, and osteoclast surface to bone surface. In vitro osteoclastogenesis and bone resorbing activity were dose-dependently reduced by NF-kappa B inhibitor S1627. Taken collectively, our results suggest that NF-kappa B inhibitors are effective in treating bone-related diseases due to their dual anabolic and antiresorptive activities. (Endocrinology 151: 4626-4634, 2010)