The loss of STAT3 in mature osteoclasts has detrimental effects on bone structure
The loss of STAT3 in mature osteoclasts has detrimental effects on bone structure
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DOI：
10.1371/journal.pone.0236891
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发表时间：
2020-07-30
期刊：
影响因子：
3.7
通讯作者：
Li, Jiliang
中科院分区：
文献类型：
--
作者：
Davidson, Rebecca K.;Himes, Evan R.;Li, Jiliang
信号转导子和转录激活子3（STAT 3）最近已被证明参与骨发育，并与骨疾病如约伯综合征有关。多年来，人们已经知道骨骼的生长和变化在性别之间是不同的，男性骨骼往往比女性骨骼具有更高的骨量，而老年女性往往比老年男性以更快的速度失去骨量。先前的研究使用成骨细胞中特异性缺失Stat 3的条件性敲除小鼠显示，两种性别都表现出骨矿物质密度（BMD）和强度降低。使用Cre-Lox系统与组织蛋白酶K启动子驱动Cre靶向成熟破骨细胞（STAT 3-cKO小鼠）中Stat 3基因的缺失，我们观察到8周龄STAT 3-cKO雌性股骨与同窝对照（CN）雌性相比表现出显著较低的BMD和骨矿物质含量（BMC）。在雄性敲除和雄性CN股骨之间观察到的BMD和BMC没有差异。然而，显微计算机断层扫描（mu CT）分析显示，雄性和雌性STAT 3-cKO小鼠的骨体积/组织体积（BV/TV）均显著降低。股骨远端的骨组织形态计量学分析进一步揭示了骨形成速率和矿化表面/骨表面（MS/BS）的降低，雌性而非雄性STAT 3-cKO小鼠的破骨细胞表面显著降低。在敲低STAT 3的骨肉瘤细胞系中分析基因表达显示，许多受雌激素受体直接调控的基因上调。这些数据共同表明，STAT 3的调节在男性和女性破骨细胞中不同，破骨细胞中STAT 3的失活对女性骨转换的影响大于男性，表明破骨细胞生成中STAT 3信号通路的复杂性。靶向STAT 3途径的药物可用于治疗疾病，如约伯综合征和骨质疏松症。
Signal Transducer and Activator of Transcription 3 (STAT3) has recently been shown to be involved in bone development and has been implicated in bone diseases, such as Job's Syndrome. Bone growth and changes have been known for many years to differ between sexes with male bones tending to have higher bone mass than female bones and older females tending to lose bone mass at faster rates than older males. Previous studies using conditional knock mice withStat3specifically deleted from the osteoblasts showed both sexes exhibited decreased bone mineral density (BMD) and strength. Using the Cre-Lox system with Cathepsin K promotor driving Cre to target the deletion of theStat3gene in mature osteoclasts (STAT3-cKO mice), we observed that 8-week old STAT3-cKO female femurs exhibited significantly lower BMD and bone mineral content (BMC) compared to littermate control (CN) females. There were no differences in BMD and BMC observed between male knock-out and male CN femurs. However, micro-computed tomography (mu CT) analysis showed that both male and female STAT3-cKO mice had significant decreases in bone volume/tissue volume (BV/TV). Bone histomorphometry analysis of the distal femur, further revealed a decrease in bone formation rate and mineralizing surface/bone surface (MS/BS) with a significant decrease in osteoclast surface in female, but not male, STAT3-cKO mice. Profiling gene expression in an osteoclastic cell line with a knockdown of STAT3 showed an upregulation of a number of genes that are directly regulated by estrogen receptors. These data collectively suggest that regulation of STAT3 differs in male and female osteoclasts and that inactivation of STAT3 in osteoclasts affects bone turnover more in females than males, demonstrating the complicated nature of STAT3 signaling pathways in osteoclastogenesis. Drugs targeting the STAT3 pathway may be used for treatment of diseases such as Job's Syndrome and osteoporosis.