间歇性低氧调控骨髓微环境NFkB-HIF1a通路及其对骨代谢的影响

Abstracts: Obstructive Sleep Apnea-Hypopnea Syndrome(OSAHS) is a well-recognized clinical respiration disorder during sleep which results in recurrent hypoxemia. It has been discoveried that bone mineral density of femoral neck in OSAHS patients were negatively corralated with Apnea hypopnea index(AHI). OSAHS, characterized with intermittent hypoxemia,may exert a positive impact on NFkB signal pathway and down-regulate the expression of HIF1a.Thus we propose that intermittent hypoxemia may inhibit bone metabolism through regulation of NFkB-HIF1a pathway in bone barrow. According to this, our primary goals are to (1) clarify the proliferation and differentiation change as well as the expression change of NFkB、PDK1、HK2 of bone marrow stem cells (BMSC) when overexpression or down-regulation HIF1a under normoxia 、intermittent hypoxemia and persistent hypoxemia ; (2) testify the oxygen metabolism change in osteoblasts(OB) and osteoclasts(OC) so as to bone turnover change under three different oxygen concentration; (3) elucidate the proliferation and differentiation change of bmsc overexpression or down-regulation HIF1a when co-culture with OB and OC under three different oxygen concentration; (3)explain how the expression change of NFkB、HIF1a effect bmsc differentiation throuh analysis of BMSC specific overexpression HIF1a transgenetic mice under intermittent hypoxemia. We object to find out the possible mechanisms of osteoporosis in OSAHS.

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是以间歇性低氧血症为特征的睡眠呼吸调节障碍疾病。本研究前期工作发现OSAHS患者股骨颈骨密度随睡眠呼吸暂停低通气指数（AHI）升高呈逐渐下降。间歇性低氧可激活OSAHS患者体内NFkB炎症信号通路，下调骨髓间充质干细胞（BMSC）HIF1a的表达，故推测间歇性低氧通过调控骨髓微环境NFkB-HIF1a通路抑制骨代谢。本实验将观察HIF1a敲除、过表达的BMSC在常氧、间歇性低氧、持续性低氧下增殖分化的变化，及NFkB、PDK1、HK2的表达改变，明确三种不同氧环境下骨转化改变。并在不同氧浓度模式下共培养HIF1a敲除、过表达的BMSC、OB、OC，分析BMSC过表达HIF1a的转基因小鼠在间歇性低氧环境中NFkB、HIF1a的表达改变对BMSC分化的作用。通过探讨慢性间歇性低氧下骨量丢失的机制，以期了解人类OSAHS导致骨量丢失的发病机理。

阻塞性睡眠呼吸暂停低通气综合征（OSAHS）是以间歇性低氧血症为特征的睡眠呼吸调节障碍疾病。本研究发现：OSAHS患者股骨颈骨密度随睡眠呼吸暂停低通气指数（AHI）升高呈逐渐下降。间歇性低氧可激活OSAHS患者体内NFkB炎症信号通路，下调骨髓间充质干细胞（BMSC）HIF1a的表达，故推测间歇性低氧通过调控骨髓微环境NFkB-HIF1a通路抑制骨代谢。本实验发现：HIF1a能显著上调与骨分化相关的因子（ALP、OCN、Runx2）mRNA的表达，促进与糖酵解相关的因子（PDK1、LDHA）表达、显著抑制脂代谢相关的因子（PPARγ、FASN、SCD1）mRNA的表达；过表达NFKB1后， HIF1amRNA水平受到抑制，与骨分化相关的因子（ALP、OCN、OPN）和与糖酵解相关的因子（PDK1、LDHA）显著被抑制，与脂质代谢相关的因子（PPARγ、FASN、SCD1）显著上调。.本研究的实验结果为OSAHS的并发症开辟了新的视野，为OSAHS及骨质疏松的临床诊治提供了新的理论依据。相关研究已经发表SIC论文1篇。