Chang Jia, Wang Zhuo, Tang Eric, Fan Zhipeng, McCauley Laurie, Franceschi Renny, Guan Kunliang, Krebsbach Paul H, Wang Cun-Yu
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
Nat Med. 2009 Jun;15(6):682-9. doi: 10.1038/nm.1954.
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.
相对于骨吸收而言，骨形成的失衡会导致骨质疏松症和炎性骨病中出现的净骨量流失。尽管人们已经清楚地知道骨吸收是如何被刺激的，但介导骨形成受损的分子机制却知之甚少。在这里，我们表明，在分化的成骨细胞中对核因子-κB（NF-κB）的内源性抑制剂κB激酶（IKK）进行时间和阶段特异性抑制，可显著增加年轻小鼠的小梁骨量和骨矿物质密度，而不影响破骨细胞活性。此外，在分化的成骨细胞中抑制IKK-NF-κB可维持骨形成，从而预防成年小鼠卵巢切除诱导的骨质疏松性骨量流失。抑制IKK-NF-κB可增强Fos相关抗原-1（Fra-1）的表达，Fra-1是一种在体外和体内参与骨基质形成的重要转录因子。综上所述，我们的结果表明，靶向IKK-NF-κB可能有助于在骨质疏松症和其他骨病的治疗中促进骨形成。
