Inhibition of osteoblastic bone formation by nuclear factor-kappaB.
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 kappaB kinase (IKK)--nuclear factor-kappaB (NF-kappaB) in differentiated osteoblasts substantially increases trabecular bone mass and bone mineral density without affecting osteoclast activities in young mice. Moreover, inhibition of IKK-NF-kappaB in differentiated osteoblasts maintains bone formation, thereby preventing osteoporotic bone loss induced by ovariectomy in adult mice. Inhibition of IKK-NF-kappaB 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-kappaB may help to promote bone formation in the treatment of osteoporosis and other bone diseases.
Chang
Jia
J
Division of Oral Biology and Medicine, Laboratory of Molecular Signaling, School of Dentistry and Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, California, USA
Wang
Zhuo
Z
Tang
Eric
E
Fan
Zhipeng
Z
McCauley
Laurie
L
Franceschi
Renny
R
Guan
Kunliang
K
Krebsbach
Paul H
PH
Wang
Cun-Yu
CY
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D010012:Osteogenesis; D010024:Osteoporosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D000099169:Fos-Related Antigen 1
D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D000099169:Fos-Related Antigen 1