Stat3 in osteocytes mediates osteogenic response to loading
Stat3 in osteocytes mediates osteogenic response to loading
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DOI：
10.1016/j.bonr.2019.100218
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发表时间：
2019-12-01
期刊：
影响因子：
2.5
通讯作者：
Li, Jiliang
中科院分区：
文献类型：
--
作者：
Corry, Kylie A.;Zhou, Hongkang;Li, Jiliang
信号转导子和转录激活子3（Stat 3）是参与许多不同细胞类型（包括骨细胞）中的信号传导的Stat蛋白家族的成员。骨细胞被认为是骨中主要的力学感受细胞，因为它们复杂的树突状网络能够感知物理力的变化并协调破骨细胞和成骨细胞的反应。我们通过使用Dmp-1（8 kb）-Cre启动子（Stat 3cKO小鼠）在这些细胞中产生缺乏Stat 3的小鼠来检查Stat 3在骨细胞中的作用。与年龄匹配的同窝对照组相比，任何性别（18周龄）的Stat 3cKO小鼠均表现出骨形成指数降低、成骨细胞减少和破骨细胞增加以及材料性质改变，但骨矿物质密度（BMD）或含量没有可检测到的变化骨小梁或皮质骨。此外，任一性别的Stat 3cKO小鼠显示出显著降低的负荷诱导的骨形成。此外，在体外用WP 1066药理学抑制骨细胞中的Stat 3阻断了由ATP诱导的细胞溶质钙的增加，ATP是细胞对剪切应力的反应的介质。WP1066还增加了培养的MLO-Y 4骨细胞中活性氧（ROS）的产生。这些数据表明，Stat 3是骨细胞接受的机械信号的关键介质，并表明骨细胞Stat 3是刺激骨愈合的潜在治疗靶点。
Signal transducer and activator of transcription 3 (Stat3) is a member of the Stat family of proteins involved in signaling in many different cell types, including osteocytes. Osteocytes are considered major mechanosensing cells in bone due to their intricate dendritic networks able to sense changes in physical force and to orchestrate the response of osteoclasts and osteoblasts. We examined the role of Stat3 in osteocytes by generating mice lacking Stat3 in these cells using the Dmp-1(8kb)-Cre promoter (Stat3cKO mice). Compared to age-matched littermate controls, Stat3cKO mice of either sex (18 weeks old) exhibit reduced bone formation indices, decreased osteoblasts and increased osteoclasts, and altered material properties, without detectable changes in bone mineral density (BMD) or content of either trabecular or cortical bone. In addition, Stat3cKO mice of either sex show significantly decreased load-induced bone formation. Furthermore, pharmacologic inhibition of Stat3 in osteocytes in vitro with WP1066 blocked the increase in cytosolic calcium induced by ATP, a mediator of the cellular responses to sheer stress. WP1066 also increased reactive oxygen species (ROS) production in cultured MLO-Y4 osteocytes. These data demonstrate that Stat3 is a critical mediator of mechanical signals received by osteocytes and suggest that osteocytic Stat3 is a potential therapeutic target to stimulate bone anabolism.