A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss
A distinctive role of the leukotriene B4 receptor BLT1 in osteoclastic activity during bone loss
复制标题
DOI：
10.1073/pnas.0905209106
复制
发表时间：
2009-12-15
影响因子：
11.1
通讯作者：
Shimizu, Takao
中科院分区：
文献类型：
--
作者：
Hikiji, Hisako;Ishii, Satoshi;Shimizu, Takao
虽然白三烯B-4 （LTB4）在多种炎症性疾病中产生，但其在骨代谢中的功能尚不清楚。我们利用缺乏高亲和力LTB4受体BLT1的小鼠，评估了BLT1在卵巢切除术和脂多糖诱导的骨质流失两种骨吸收模型的发展中的作用。通过观察骨矿物质含量和骨形态计量参数，我们发现blt1缺失小鼠的骨吸收在两种模型中都明显减弱。此外，与野生型破骨细胞相比，blt1缺失小鼠的破骨细胞的钙吸收活性降低。破骨细胞表达BLT1，而不表达低亲和力LTB4受体BLT2，并产生LTB4。LTB4通过BLT1-Gi蛋白- rac1信号通路改变破骨细胞的细胞形态。鉴于破骨细胞形态与破骨细胞活性之间的因果关系，这些研究结果表明，自分泌/旁分泌LTB4通过BLT1-Gi蛋白- rac1信号通路增加破骨细胞活性。抑制BLT1功能可能是预防骨吸收疾病的一种策略。
Although leukotriene B-4 (LTB4) is produced in various inflammatory diseases, its functions in bone metabolism remain unknown. Using mice deficient in the high-affinity LTB4 receptor BLT1, we evaluated the roles of BLT1 in the development of two bone resorption models, namely bone loss induced by ovariectomy and lipopolysaccharide. Through observations of bone mineral contents and bone morphometric parameters, we found that bone resorption in both models was significantly attenuated in BLT1-deficient mice. Furthermore, osteoclasts from BLT1-deficient mice showed reduced calcium resorption activities compared with wild-type osteoclasts. Osteoclasts expressed BLT1, but not the low-affinity LTB4 receptor BLT2, and produced LTB4. LTB4 changed the cell morphology of osteoclasts through the BLT1-Gi protein-Rac1 signaling pathway. Given the causal relationship between osteoclast morphology and osteoclastic activity, these findings suggest that autocrine/paracrine LTB4 increases the osteoclastic activity through the BLT1-Gi protein-Rac1 signaling pathway. Inhibition of BLT1 functions may represent a strategy for preventing bone resorption diseases.