Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts.
Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts.
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DOI：
10.1359/jbmr.090806
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Mishina Y
中科院分区：
文献类型：
--
作者：
Kamiya N;Kobayashi T;Mochida Y;Yu PB;Yamauchi M;Kronenberg HM;Mishina Y
骨形态发生蛋白（BMP）和Wnt信号通路都在调节骨量中发挥重要作用。然而，在成骨细胞中，这些途径之间的分子相互作用知之甚少。我们最近报道了BMP受体IA型（BMPRIA）的成骨细胞靶向条件敲除（cKO）导致胚胎发育期间骨量增加，其中Sost作为BMPRIA的下游效应物的表达减少导致Wnt/β-catenin信号传导增加。在这里，我们报告Bmpr1a cKO小鼠在断奶期表现出骨量增加，Wnt报告基因TOPGAL小鼠和TOPFLASH荧光素酶评估了Wnt/β-catenin信号增强的证据。与BMPRIA信号对Wnt通路的负调控一致，用smad依赖性BMP信号抑制剂dorsomorphin治疗成骨细胞可增强Wnt信号。除Sost外，Wnt抑制剂Dkk1在cKO骨中也下调。BMP2处理上调dkk1和Sost的表达水平，而Noggin则下调dkk1和Sost的表达水平。此外，在小鼠中表达组成型活性Bmpr1a转基因导致Dkk1和Sost上调，并部分恢复Bmpr1a cKO骨表型。这些效应物受丝裂原活化蛋白激酶（MAPK） p38的差异调节，因为SB202190预处理成骨细胞可阻断bmp2诱导的Dkk1表达，但不能阻断Sost。这些结果表明，成骨细胞中的BMPRIA负调控内源性骨量和Wnt/β-catenin信号通路，这种调控可能是由Sost和Dkk1的活性介导的。本研究强调了成骨细胞中BMP和Wnt信号级联之间的几种相互作用，这些相互作用可能适用于骨密度改变的治疗干预。©2010美国骨与矿物研究学会
The bone morphogenetic protein (BMP) and Wnt signaling pathways both contribute essential roles in regulating bone mass. However, the molecular interactions between these pathways in osteoblasts are poorly understood. We recently reported that osteoblast-targeted conditional knockout (cKO) of BMP receptor type IA (BMPRIA) resulted in increased bone mass during embryonic development, where diminished expression of Sost as a downstream effector of BMPRIA resulted in increased Wnt/β-catenin signaling. Here, we report that Bmpr1a cKO mice exhibit increased bone mass during weanling stages, again with evidence of enhanced Wnt/β-catenin signaling as assessed by Wnt reporter TOPGAL mice and TOPFLASH luciferase. Consistent with negative regulation of the Wnt pathway by BMPRIA signaling, treatment of osteoblasts with dorsomorphin, an inhibitor of Smad-dependent BMP signaling, enhanced Wnt signaling. In addition to Sost, Wnt inhibitor Dkk1 also was downregulated in cKO bone. Expression levels of Dkk1and Sost were upregulated by BMP2 treatment and downregulated by Noggin. Moreover, expression of a constitutively active Bmpr1a transgene in mice resulted in the upregulation of both Dkk1 and Sost and partially rescued the Bmpr1a cKO bone phenotype. These effectors are differentially regulated by mitogen-activated protein kinase (MAPK) p38 because pretreatment of osteoblasts with SB202190 blocked BMP2-induced Dkk1 expression but not Sost. These results demonstrate that BMPRIA in osteoblasts negatively regulates endogenous bone mass and Wnt/β-catenin signaling and that this regulation may be mediated by the activities of Sost and Dkk1. This study highlights several interactions between BMP and Wnt signaling cascades in osteoblasts that may be amenable to therapeutic intervention for the modification of bone mass density. © 2010 American Society for Bone and Mineral Research
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