A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction
A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction
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DOI：
10.1074/jbc.m702231200
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发表时间：
2007-08-31
影响因子：
4.8
通讯作者：
Bellido, Teresita
中科院分区：
文献类型：
--
作者：
Aguirre, J. Ignacio;Plotkin, Lilian I.;Bellido, Teresita
骨骼通过一个广泛的机械传导网络感知并适应以满足力学需求，该网络由骨细胞（被矿物质包埋的前成骨细胞）及其细胞质突起组成，骨细胞通过这些突起与骨表面的成骨细胞和破骨细胞进行通讯。机械刺激通过激活细胞外信号调节激酶（ERKs）促进骨细胞（和成骨细胞）的存活。雌激素具有类似的作用，有趣的是，在缺乏雌激素受体α（ERα）或雌激素受体β（ERβ）的小鼠中，骨骼对机械力的适应性反应存在缺陷。我们报道，在ERα和ERβ都被敲除或敲低的骨细胞和成骨细胞中，拉伸不会激活ERKs，而通过转染两种人源ER中的任何一种可部分逆转这种情况，通过转染两种受体则可完全逆转。通过转染任一受体的配体结合域（E）或一种不结合雌激素的ERα突变体，也可恢复对拉伸的ERK激活反应。此外，通过转染靶向细胞膜而非细胞核的Eα可恢复机械反应性，而细胞膜定位受损或与小窝蛋白 - 1结合受损的ERα突变体在拉伸时无法激活ERK。最后，ER拮抗剂ICI 182,780可消除ERK激活以及机械刺激的抗凋亡作用。我们得出结论，除了作为雌激素作用的配体依赖性介质外，ERs还以一种不依赖配体的方式参与将机械力转导为骨细胞中的促存活信号。
Bone senses and adapts to meet mechanical needs by means of an extensive mechanotransduction network comprising osteocytes ( former osteoblasts entrapped in mineral) and their cytoplasmic projections through which osteocytes communicate with osteoblasts and osteoclasts on the bone surface. Mechanical stimulation promotes osteocyte ( and osteoblast) survival by activating the extracellular signal-regulated kinases, ERKs. Estrogens have similar effects and, intriguingly, the adaptive response of bone to mechanical forces is defective in mice lacking estrogen receptor ( ER) alpha or ER beta. We report that ERKs are not activated by stretching in osteocytic and osteoblastic cells in which both ER alpha and ER beta have been knocked out or knocked down and this is reversed partially by transfection of either one of the two human ERs and fully by transfection of both receptors. ERK activation in response to stretching is also recovered by transfecting the ligand-binding domain ( E) of either receptor or an ER alpha mutant that does not bind estrogens. Furthermore, mechano-responsiveness is restored by transfecting the E alpha targeted to the plasma membrane, but not to the nucleus, whereas ER alpha mutants with impaired plasma membrane localization or binding to caveolin-1 fail to confer ERK activation in response to stretching. Lastly, the ER antagonist ICI 182,780 abrogates ERK activation and the anti-apoptotic effect of mechanical stimulation. We conclude that in addition to their role as ligand-dependent mediators of the effects of estrogens, the ERs participate in the transduction of mechanical forces into pro-survival signaling in bone cells, albeit in a ligand-independent manner.