Chiang C Y, Kyritsis G, Graves D T, Amar S
Department of Periodontology and Oral Biology, School of Dental Medicine, Boston University, Boston, Massachusetts 02118, USA.
Infect Immun. 1999 Aug;67(8):4231-6. doi: 10.1128/IAI.67.8.4231-4236.1999.
The present study was undertaken to test the hypothesis that tumor necrosis factor (TNF) and/or interleukin-1 (IL-1) activity mediates lipopolysaccharide (LPS)-induced bone resorption in vivo. To test this hypothesis, Escherichia coli LPS or Porphyromonas gingivalis LPS was injected into the subcutaneous tissues overlying mouse calvariae. Histological sections, prepared from the center of the lesion, were stained for tartrate-resistant acid phosphatase, and histomorphometric analysis was performed to quantify the osteoclast number and the area of bone resorption. In time course experiments using normal mice, a peak of bone resorption occurred 5 days after endotoxin stimulation. In dose-response experiments, IL-1 receptor type 1 deletion (IL-1R(-/-)), TNF double-receptor p55/p75 deletion (TNF p55(-/-)/p75(-/-)), combined TNF p55 and IL-1 receptor type 1 deletion (TNF p55(-/-)/IL-1R(-/-)), and IL-1beta-converting enzyme-deficient (ICE(-/-)) mice and the respective wild-type mice were injected with 500, 100, or 20 micrograms of P. gingivalis LPS and sacrificed 5 days after LPS injection. At the highest dose (500 micrograms), significant decreases in osteoclast number occurred in mutant mice compared to wild-type mice: (i) a 64% reduction for the TNF p55(-/-)/IL-1R(-/-) mice, (ii) a 57% reduction for the IL-1R(-/-) mice, (iii) a 41% reduction for the TNF p55(-/-)/p75(-/-) mice, and (iv) a 38% reduction for the ICE(-/-) mice. At the two lower doses, bone resorption was apparent but no significant differences between mutant and wild-type animals were observed. The present data indicate that at higher doses, LPS-induced bone resorption is substantially mediated by IL-1 and TNF receptor signaling. Furthermore, IL-1 receptor signaling appears to be slightly more important than TNF receptor signaling. At lower LPS doses, other pathways leading to osteoclast activity that are independent of TNF and IL-1 are involved.
本研究旨在验证肿瘤坏死因子（TNF）和/或白细胞介素-1（IL-1）活性介导体内脂多糖（LPS）诱导的骨吸收这一假说。为验证该假说，将大肠杆菌LPS或牙龈卟啉单胞菌LPS注射到小鼠颅骨上方的皮下组织中。从病变中心制备组织学切片，用抗酒石酸酸性磷酸酶染色，并进行组织形态计量分析以量化破骨细胞数量和骨吸收面积。在使用正常小鼠的时间进程实验中，内毒素刺激后5天出现骨吸收峰值。在剂量反应实验中，给1型IL-1受体缺失（IL-1R(-/-)）、TNF双受体p55/p75缺失（TNF p55(-/-)/p75(-/-)）、TNF p55和1型IL-1受体联合缺失（TNF p55(-/-)/IL-1R(-/-)）以及IL-1β转换酶缺陷（ICE(-/-)）小鼠和各自的野生型小鼠注射500、100或20微克牙龈卟啉单胞菌LPS，并在注射LPS后5天处死。在最高剂量（500微克）时，与野生型小鼠相比，突变小鼠的破骨细胞数量显著减少：（i）TNF p55(-/-)/IL-1R(-/-)小鼠减少64%，（ii）IL-1R(-/-)小鼠减少57%，（iii）TNF p55(-/-)/p75(-/-)小鼠减少41%，（iv）ICE(-/-)小鼠减少38%。在两个较低剂量时，骨吸收明显，但未观察到突变小鼠和野生型动物之间的显著差异。目前的数据表明，在较高剂量下，LPS诱导的骨吸收主要由IL-1和TNF受体信号传导介导。此外，IL-1受体信号传导似乎比TNF受体信号传导稍微更重要。在较低的LPS剂量下，涉及其他独立于TNF和IL-1导致破骨细胞活性的途径。
