In vivo mechanical loading rapidly activates β-catenin signaling in osteocytes through a prostaglandin mediated mechanism.
In vivo mechanical loading rapidly activates β-catenin signaling in osteocytes through a prostaglandin mediated mechanism.
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DOI：
10.1016/j.bone.2015.03.019
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发表时间：
2015-07
期刊：
影响因子：
4.1
通讯作者：
Johnson, M. L.
中科院分区：
文献类型：
--
作者：
Lara-Castillo, N.;Kim-Weroha, N. A.;Kamel, M. A.;Javaheri, B.;Ellies, D. L.;Krumlauf, R. E.;Thiagarajan, G.;Johnson, M. L.
骨骼对负荷的反应似乎是通过激活Wnt/β-catenin信号通路介导的，骨细胞一直被认为是骨骼中主要的机械感觉细胞。为了研究体内骨骼和细胞类型的机械反应动力学，我们对17周龄雌性TOPGAL小鼠进行了前臂负荷。加载后1小时，β-catenin信号仅在嵌入的骨细胞中观察到，而不是在成骨细胞中观察到，并在24小时内扩散到其他骨细胞，最终扩散到骨表面的细胞。这种1小时的早期激活似乎独立于受体（Lrp5/6）介导的激活，因为它发生在抑制剂sclerostin和/或Dkk1存在的情况下。COX-2抑制剂卡洛芬阻断了β-catenin信号的激活和加载后硬化蛋白阳性骨细胞的下降，这意味着前列腺素的重要作用。在体外，在MLO-Y4骨细胞样细胞中，PI3K/Akt的激活被证明是β-catenin核转位从前列腺素下游转位所必需的，这支持了这一机制。我们还检测了β-catenin信号传导的下游靶点，硬化蛋白和Dkk1，发现在体内骨细胞中，在加载后24小时显著下调。骨细胞最初激活的模式似乎是随机的，为了理解这种异质性表达，我们开发了一种新的尺骨应变场有限元模型，该模型预测了骨细胞经历的高度可变的局部应变大小。综上所述，体内和体外模型均显示β-catenin通过前列腺素的早期释放对负荷的响应而快速激活，并且骨内应变场的异质性极大，导致体内骨细胞β-catenin通路的激活不均匀。
The response of the skeleton to loading appears to be mediated through the activation of the Wnt/β-catenin signaling pathway and osteocytes have long been postulated to be the primary mechanosensory cells in bone. To examine the kinetics of the mechanoresponse of bone and cell types involved in the in vivo, we performed forearm loading of 17-week-old female TOPGAL mice. β-catenin signaling was observed only in embedded osteocytes, not osteoblasts, at 1 hour post loading, spreading to additional osteocytes and finally to cells on the bone surface by 24 hrs. This early activation at 1 hour appeared to be independent of receptor (Lrp5/6) mediated activation as it occurred in the presence of the inhibitors sclerostin and/or Dkk1. The COX-2 inhibitor, Carprofen, blocked the activation of β-catenin signaling and decline in sclerostin positive osteocytes post-loading implying an important role for prostaglandin. In vitro, PI3K/Akt activation was shown to be required for β-catenin nuclear translocation downstream from prostaglandin in MLO-Y4 osteocyte-like cells supporting this mechanism. Downstream targets of β-catenin signaling, sclerostin and Dkk1, were also examined and found to be significantly down regulated in osteocytes in vivo at 24 hours post-loading. The pattern of initially activated osteocytes appeared random and in order to understand this heterogeneous expression, a novel finite element model of the strain field in the ulna was developed, which predicts highly variable local magnitudes of strain experienced by osteocytes. In summary, both in vivo and in vitro models show the rapid activation of β-catenin in response to load through the early release of prostaglandin and that strain fields in the bone are extremely heterogeneous resulting in heterogeneous activation of the β-catenin pathway in osteocytes in vivo.
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影响因子：
6.2
作者：
Kitase, Yukiko;Barragan, Leonardo;Qing, Hai;Kondoh, Shino;Jiang, Jean X.;Johnson, Mark L.;Bonewald, Lynda F.
通讯作者：
Bonewald, Lynda F.
影响因子：
4.1
作者：
Kalajzic, Ivo;Matthews, Brya G.;Torreggiani, Elena;Harris, Marie A.;Pajevic, Paola Divieti;Harris, Stephen E.
通讯作者：
Harris, Stephen E.
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
4.8
作者：
Armstrong, Victoria J.;Muzylak, Mariusz;Lanyon, Lance E.
通讯作者：
Lanyon, Lance E.
影响因子：
4.8
作者：
Cherian, PP;Cheng, BX;Jiang, JX
通讯作者：
Jiang, JX