Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development.
Gpr177, a novel locus for bone mineral density and osteoporosis, regulates osteogenesis and chondrogenesis in skeletal development.
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DOI：
10.1002/jbmr.1830
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发表时间：
2013-05
影响因子：
6.2
通讯作者：
Hsu, Wei
中科院分区：
文献类型：
--
作者：
Maruyama, Takamitsu;Jiang, Ming;Hsu, Wei
人类遗传分析最近确定Gpr 177作为骨矿物质密度和骨质疏松症的易感位点。因此，确定该基因的未知功能对于进一步了解骨骼发育和疾病非常重要。由Gpr 177编码的蛋白表现出类似于果蝇Wls/Evi/Srt的调节Wnt运输的能力。由于在Wnt调控中的关键作用，Gpr 177可能是骨骼发生的几个关键步骤所必需的。为了克服与小鼠中Gpr 177失活相关的早期致死性，利用条件性基因缺失来评估其功能性。在这里，我们报告了四种不同的小鼠模型，Gpr 177缺陷的各种骨骼发生细胞类型的代。Gpr 177的丢失严重损害颅面和身体骨骼的发育，分别证明了其对膜内和软骨内骨化的需求。骨骼前体的扩张及其分化成成骨细胞和软骨细胞的缺陷表明，Wnt的产生和Gpr 177介导的信号传导是不可替代的。由于Gpr 177消融损害了Wnt蛋白的分泌，因此我们确定了它们对骨生成和软骨生成至关重要的来源。Wnt信号在不同细胞类型之间的交叉是精心策划的，并且是骨骼发生所必需的。我们的研究结果导致了一个拟议的机制，Gpr 177控制骨骼发育，通过自分泌和旁分泌Wnt信号的调制在一个谱系特异性的方式。
Human genetic analysis has recently identified Gpr177 as a susceptibility locus for bone-mineral-density and osteoporosis. Determining the unknown function of this gene is therefore extremely important to further our knowledge base of skeletal development and disease. The protein encoded by Gpr177 exhibits an ability to modulate the trafficking of Wnt similar to the Drosophila Wls/Evi/Srt. Because of a critical role in Wnt regulation, Gpr177 might be required for several key steps of skeletogenesis. To overcome the early lethality associated with the inactivation of Gpr177 in mice, conditional gene deletion is utilized to assess its functionality. Here we report the generation of four different mouse models with Gpr177 deficiency in various skeletogenic cell types. The loss of Gpr177 severely impairs development of the craniofacial and body skeletons, demonstrating its requirement for intramembranous and endochondral ossifications, respectively. Defects in the expansion of skeletal precursors and their differentiation into osteoblasts and chondrocytes suggest that Wnt production and signaling mediated by Gpr177 cannot be substituted. Because the Gpr177 ablation impairs the secretion of Wnt proteins, we therefore identify their sources essential for osteogenesis and chondrogenesis. The intercross of Wnt signaling between distinct cell types is carefully orchestrated and necessary for skeletogenesis. Our findings lead to a proposed mechanism by which Gpr177 controls skeletal development through modulation of autocrine and paracrine Wnt signals in a lineage-specific fashion.
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影响因子：
7.3
作者：
Maruyama T;Mirando AJ;Deng CX;Hsu W
通讯作者：
Hsu W
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
0.7
作者：
Liu, F;Woitge, HW;Kream, BE
通讯作者：
Kream, BE
影响因子：
6.2
作者：
Ferrari, SL;Karasik, D;Kiel, DP
通讯作者：
Kiel, DP