Wnt/β-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor α
Wnt/β-catenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor α
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DOI：
10.1074/jbc.m703224200
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发表时间：
2007-07-13
影响因子：
4.8
通讯作者：
Lanyon, Lance E.
中科院分区：
文献类型：
--
作者：
Armstrong, Victoria J.;Muzylak, Mariusz;Lanyon, Lance E.
Wnt/ β -连环蛋白通路与骨细胞对其机械环境的反应有关。这种反应是骨细胞调节骨结构以维持骨强度的机制的起源。骨质疏松症是这一机制最普遍的失败。男性和女性骨质疏松性骨质流失的程度与生物可利用雌激素有关。在成骨细胞ROS 17/2.8细胞和原代成骨细胞培养中，单次短时间的动态机械应变，以及糖原合酶激酶-3 β (GSK-3 β)抑制剂LiCl，增加了活化β -连环蛋白的核积累，并刺激了TCF/LEF报告细胞活性。这种作用被雌激素受体（ER）调节剂ICI 182780和他莫昔芬阻断，并且在缺乏ER α的小鼠的原代成骨细胞培养中不存在。从野生型小鼠胫骨中提取的总RNA中提取25000个基因，在体内加载24小时内的微阵列表达数据显示，在加载和对侧未加载的骨骼中，有10个基因参与了Wnt通路的差异基因调控。只有2个基因参与了缺乏ER α小鼠的胫骨负荷（ER α(-/-)）。这些数据表明，Wnt/ β -连环蛋白信号有助于骨细胞对机械应变的早期反应，其有效性需要内质网α。骨细胞对骨负荷反应的有效性降低，与雌激素相关的内质网α下降有关，可能导致男性和女性骨质疏松症患者无法维持结构适当的骨量。
The Wnt/beta-catenin pathway has been implicated in bone cell response to their mechanical environment. This response is the origin of the mechanism by which bone cells adjust bone architecture to maintain bone strength. Osteoporosis is the most widespread failure of this mechanism. The degree of osteoporotic bone loss in men and women is related to bio-available estrogen. Here we report that in osteoblastic ROS 17/2.8 cells and primary osteoblast cultures, a single short period of dynamic mechanical strain, as well as the glycogen synthase kinase-3 beta (GSK-3 beta) inhibitor LiCl, increased nuclear accumulation of activated beta-catenin and stimulated TCF/LEF reporter activity. This effect was blocked by the estrogen receptor ( ER) modulators ICI 182,780 and tamoxifen and was absent in primary osteoblast cultures from mice lacking ER alpha. Microarray expression data for 25,000 genes from total RNA extracted from tibiae of wild-type mice within 24 h of being loaded in vivo showed differential gene regulation between loaded and contralateral non-loaded bones of 10 genes established to be involved in the Wnt pathway. Only 2 genes were involved in loaded tibiae from mice lacking ER alpha (ER alpha(-/-)). Together these data suggest that Wnt/beta-catenin signaling contributes to bone cell early responses to mechanical strain and that its effectiveness requires ER alpha. Reduced effectiveness of bone cell responses to bone loading, associated with estrogen-related decline in ER alpha, may contribute to the failure to maintain structurally appropriate bone mass in osteoporosis in both men and women.