Section of Pharmacology, Department of Hard Tissue Engineering, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
J Periodontal Res. 2011 Apr;46(2):280-4. doi: 10.1111/j.1600-0765.2010.01333.x. Epub 2010 Dec 29.
Nuclear factor-κB (NF-κB) is activated at sites of inflammation in many diseases, including periodontitis. Nuclear factor-κB induces the transcription of proinflammatory cytokines, resulting in increased osteoclastogenesis and bone resorption. Recently, it has been shown that the NF-κB alternative pathway is important for maintainance of physiological bone homeostasis. Activation of this pathway is by processing of the inhibitor p100 into the active subunit p52 by nuclear factor-κB-inducing kinase (NIK). Defective NIK in aly/aly mice (NIK(aly)) causes mild osteopetrosis and blunted RANKL-stimulated osteoclastogenesis in vivo and in vitro, suggesting that NIK is necessary for basal and stimulated osteoclastogenesis. Nevertheless, the role of NIK in pathological bone resorption is not well investigated. The present study was undertaken to investigate the role of NIK in lipopolysaccharide (LPS)-induced inflammatory bone resorption using aly/aly mice.
Mice were injected with LPS over the calvariae and killed 5 d later. Calvariae were subjected to radiological analysis. Histological sections were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the number of osteoclasts and the area of bone resorption.
Lipopolysaccharide-induced inflammation was observed in wild-type and aly/+ mice but not in aly/aly mice. Lipopolysaccharide significantly reduced the calvarial bone mineral density in wild-type and aly/+ mice, whereas bone mineral density was comparable in LPS- and vehicle-injected aly/aly mice. In addition, aly/aly mice were resistant to LPS-induced bone resorption and osteoclastogenesis.
Taken together, these data show that NIK is important in the bone-destructive components of inflammation and represents a possible therapeutic target.
核因子-κB（NF-κB）在许多疾病的炎症部位被激活，包括牙周炎。NF-κB 诱导促炎细胞因子的转录，导致破骨细胞生成和骨吸收增加。最近，已经表明 NF-κB 的替代途径对于维持生理骨稳态很重要。该途径的激活是通过核因子-κB 诱导激酶（NIK）将抑制剂 p100 加工成活性亚基 p52 来实现的。aly/aly 小鼠（NIK(aly)) 中的缺陷 NIK 导致轻微的骨质增生和体内体外 RANKL 刺激的破骨细胞生成减少，表明 NIK 对于基础和刺激的破骨细胞生成是必要的。然而，NIK 在病理性骨吸收中的作用尚未得到很好的研究。本研究旨在使用 aly/aly 小鼠研究 NIK 在脂多糖（LPS）诱导的炎症性骨吸收中的作用。
将 LPS 注射到颅骨上，5 天后处死小鼠。对颅骨进行放射学分析。对组织切片进行抗酒石酸酸性磷酸酶染色，并进行组织形态计量学分析以定量破骨细胞数量和骨吸收面积。
在野生型和 aly/+ 小鼠中观察到 LPS 诱导的炎症，但在 aly/aly 小鼠中未观察到。LPS 显著降低了野生型和 aly/+ 小鼠的颅骨骨密度，而 LPS 和载体注射的 aly/aly 小鼠的骨密度相当。此外，aly/aly 小鼠对 LPS 诱导的骨吸收和破骨细胞生成具有抗性。
综上所述，这些数据表明 NIK 在炎症的骨破坏性成分中很重要，是一个可能的治疗靶点。
