Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signaling.
Oxysterol-induced osteogenic differentiation of marrow stromal cells is regulated by Dkk-1 inhibitable and PI3-kinase mediated signaling.
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DOI：
10.1002/jcb.21840
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发表时间：
2008-10-01
影响因子：
4
通讯作者：
Parhami, Farhad
中科院分区：
文献类型：
--
作者：
Amantea, Christopher M.;Kim, Woo-Kyun;Meliton, Vicente;Tetradis, Sotirios;Parhami, Farhad
关键词：
骨质疏松症及其并发症导致老年人群的发病率和死亡率，其原因是破骨细胞增加骨吸收，同时成骨细胞减少骨形成。一种被广泛接受的改善骨健康的策略是靶向成骨细胞，以通过使用骨诱导/合成代谢因子来刺激其成骨分化和骨形成特性。我们之前曾报道，特定的自然产生的氧化甾醇具有强大的成骨诱导特性，部分是通过激活骨祖细胞中的Hedgehog信号来介导的。在本报告中，我们进一步论证了氧化甾醇诱导成骨的分子机制(S)。除了激活Hedgehog信号通路外，Ox-sterol诱导的成骨分化还通过Wnt信号相关的DKK-1抑制机制来介导。用氧化甾醇处理的骨髓基质细胞显示成骨分化标记物的表达增加，同时选择性诱导Wnt靶基因的表达。这些在没有β-连环蛋白积聚或Tcf/Lef激活的情况下发生的氧固醇效应，可被Hedgehog途径抑制剂环丙胺和/或Wnt途径抑制剂DKK-1抑制。此外，PI3-Kinase信号转导的抑制剂LY 294002和Wortmanin可抑制氧固醇诱导的成骨分化和Wnt信号转导靶基因的诱导。最后，规范的Wnt信号激活剂Wnt3a和Wnt1抑制了自发性、氧固醇性和Shh诱导的骨髓基质细胞的成骨分化，提示非规范的Wnt信号通路参与了成骨分化事件。因此，成骨氧合固醇是多能间充质细胞中关键信号通路的重要小分子调节器，调节着许多发育和发育后的过程。
Osteoporosis and its complications cause morbidity and mortality in the aging population, and result from increased bone resorption by osteoclasts in parallel with decreased bone formation by osteoblasts. A widely accepted strategy for improving bone health is targeting osteoprogenitor cells in order to stimulate their osteogenic differentiation and bone forming properties through the use of osteoinductive/anabolic factors. We previously reported that specific naturally-occurring oxysterols have potent osteoinductive properties, mediated in part through activation of hedgehog signaling in osteoprogenitor cells. In the present report, we further demonstrate the molecular mechanism(s) by which oxysterols induce osteogenesis. In addition to activating the hedgehog signaling pathway, oxysterol-induced osteogenic differentiation is mediated through a Wnt signaling-related, Dkk-1-inhibitable mechanism. Bone marrow stromal cells treated with oxysterols demontrated increased expression of osteogenic differentiation markers, along with selective induced expression of Wnt target genes. These oxysterol effects, which occurred in the absence of β-catenin accumulation or TCF/Lef activation, were inhibited by the hedgehog pathway inhibitor, cyclopamine, and/or by the Wnt pathway inhibitor, Dkk-1. Furthermore, the inhibitors of PI3-Kinase signaling, LY 294002 and wortmanin, inhibited oxysterol-induced osteogenic differentiation and induction of Wnt signaling target genes. Finally, activators of canonical Wnt signaling, Wnt3a and Wnt1, inhibited spontaneous, oxysterol- and Shh-induced osteogenic differentiation of bone marrow stromal cells, suggesting the involvement of a non-canonical Wnt pathway in pro-osteogenic differentiation events. Osteogenic oxysterols are, therefore, important small molecule modulators of critical signaling pathways in pluripotent mesenchymal cells that regulate numerous developmental and post-developmental processes.
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DOI：
10.1073/pnas.0505259102
发表时间：
2005-11-29
影响因子：
11.1
作者：
Clément-Lacroix, P;Ai, MR;Rawadi, G
通讯作者：
Rawadi, G
影响因子：
8.2
作者：
Fu, Jin-Rong;Liu, Wen-Li;Zhou, Yu-Feng
通讯作者：
Zhou, Yu-Feng
影响因子：
4.8
作者：
Ghosh-Choudhury, Nandini;Mandal, Chandi Charan;Choudhury, Goutam Ghosh
通讯作者：
Choudhury, Goutam Ghosh
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：
Kanda, S;Mochizuki, Y;Kanetake, H
通讯作者：
Kanetake, H