Inhibition of osteoblastic bone formation by nuclear factor-κB

Abstract

It has been well shown that NF-κB has a crucial role in promoting the maturation of bone-resorbing osteoclasts. Now, Cun-Yu Wang and his colleagues show that it also has a role in inhibiting the function of mature bone-forming osteoblasts. They go on to show that deficiency of NF-κB specifically in osteoblasts increases bone formation and protects against bone loss in experimentally-induced osteoporosis in mice. An imbalance in bone formation relative to bone resorption results in the net bone loss that occurs in osteoporosis and inflammatory bone diseases. Although it is well known how bone resorption is stimulated, the molecular mechanisms that mediate impaired bone formation are poorly understood. Here we show that the time- and stage-specific inhibition of endogenous inhibitor of κB kinase (IKK)–nuclear factor-κB (NF-κB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK–NF-κB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK–NF-κB enhances the expression of Fos-related antigen-1 (Fra-1), an essential transcription factor involved in bone matrix formation in vitro and in vivo. Taken together, our results suggest that targeting IKK–NF-κB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.