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

Abstract

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)-κB reduces the osteoclast bone resorption. The role of NF-κB inhibitors on osteoblasts and bone formation, however, is minimal and not well investigated. Using an established NF-κB inhibitor named S1627, we demonstrated that inhibition of NF-κB 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-κB 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-κB 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-κB inhibitor S1627. Taken collectively, our results suggest that NF-κB inhibitors are effective in treating bone-related diseases due to their dual anabolic and antiresorptive activities.

Maternal Mineral and Bone Metabolism During Pregnancy, Lactation, and Post-Weaning Recovery

“…When ovariectomized, sham-operated, and intact lactating rats were each stressed by a 0.1% calcium diet, there was no difference in the reduction of femoral ash weight among the groups (32). Ovariectomy to create estradiol deficiency leads to modest and slow bone loss in rodents, and not to the rapid loss that occurs during lactation (22,34,260). Conversely, treatment with estradiol to achieve fivefold higher levels than normal during lactation blunted bone loss and caused a small decline in milk calcium (956).…”

High dose 1,25(OH)2D3 inhibits osteoblast mineralization in vitro

“…In fact the reported anti-inflammatory properties of 1,25(OH) 2 D 3 may be related, in part, to its ability to downregulate NF-κB activation. In the context of osteoblast biology however, the NF-κB signal transduction system is a pathway that we (5,7,9-12) and others (13)(14)(15)(16)(17) have reported to potently suppress osteoblastic bone formation. Indeed, TNF-α, a potent inducer of NF-κB activation, significantly reduces the basal bone formation rate leading to diminished peak bone mineral density (BMD) in mice (5).…”

Nanogel-crosslinked nanoparticles increase the inhibitory effects of W9 synthetic peptide on bone loss in a murine bone resorption model

“…35 Undecalcified sections (5 µm) were prepared using an automicrotome (Supercut 2050, Reichert-Jung, Armsberg, Germany). Some sections were stained with von Kossa stain and counterstained with a modified van Gieson method to clarify the mineralized tissue, 36,37 or were subjected to tartrate-resistant acid phosphatase (TRAP) staining. Osteoclasts were designated as TRAP-positive multinucleated cells (n2) located on the bone surface.…”