The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway
The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway
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DOI：
10.1126/scisignal.aaw3921
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发表时间：
2019-07-09
影响因子：
7.3
通讯作者：
Hinoi, Eiichi
中科院分区：
文献类型：
--
作者：
Ozaki, Kakeru;Yamada, Takanori;Hinoi, Eiichi
L型氨基酸转运蛋白1（LAT 1）由溶质载体转运蛋白7a 5（Slc 7a 5）编码，在特定细胞类型的氨基酸传感和信号传导中起着至关重要的作用，有助于癌症和神经系统疾病的发病机制。LAT 1的氨基酸底物对骨健康有直接和间接的有益作用，表明LAT 1在骨稳态中的潜在作用。在这里，我们确定了破骨细胞中的LAT 1对骨稳态很重要。在卵巢切除诱导的骨质疏松症的小鼠模型中，破骨细胞中Slc 7a 5的表达显著降低。小鼠体内破骨细胞特异性Slc 7a 5缺失导致破骨细胞活化和骨丢失，体外Slc 7a 5缺失增加破骨细胞生成。Slc 7a 5的缺失损害了破骨细胞中雷帕霉素复合物1（mTORC 1）通路的机制靶点的激活，而mTORC 1的遗传激活纠正了Slc 7a 5缺陷小鼠中破骨细胞生成和骨丢失的增强。最后，Slc 7a 5缺陷增加了活化T细胞的核因子，胞质1（Nfatc 1）的表达和NFATc 1的核积累，NFATc 1是破骨细胞功能的主要调节剂，可能分别通过经典核因子κ B途径和Akt-糖原合成酶激酶3 β信号传导轴。这些发现表明，LAT 1-mTORC 1轴通过调节破骨细胞中的NFATc 1在骨吸收和骨稳态中起关键作用，从而提供氨基酸摄入和骨骼完整性之间的分子联系。
L-type amino acid transporter 1 (LAT1), which is encoded by solute carrier transporter 7a5 (Slc7a5), plays a crucial role in amino acid sensing and signaling in specific cell types, contributing to the pathogenesis of cancer and neurological disorders. Amino acid substrates of LAT1 have a beneficial effect on bone health directly and indirectly, suggesting a potential role for LAT1 in bone homeostasis. Here, we identified LAT1 in osteoclasts as important for bone homeostasis. Slc7a5 expression was substantially reduced in osteoclasts in a mouse model of ovariectomy-induced osteoporosis. The osteoclast-specific deletion of Slc7a5 in mice led to osteoclast activation and bone loss in vivo, and Slc7a5 deficiency increased osteoclastogenesis in vitro. Loss of Slc7a5 impaired activation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in osteoclasts, whereas genetic activation of mTORC1 corrected the enhanced osteoclastogenesis and bone loss in Slc7a5-deficient mice. Last, Slc7a5 deficiency increased the expression of nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1) and the nuclear accumulation of NFATc1, a master regulator of osteoclast function, possibly through the canonical nuclear factor kappa B pathway and the Akt-glycogen synthase kinase 3 beta signaling axis, respectively. These findings suggest that the LAT1-mTORC1 axis plays a pivotal role in bone resorption and bone homeostasis by modulating NFATc1 in osteoclasts, thereby providing a molecular connection between amino acid intake and skeletal integrity.