Abstract：
Scoliosis, usually diagnosed in childhood and early adolescence, is an abnormal lateral curvature of the spine. L-type amino acid transporter 1 (LAT1), encoded by solute carrier transporter 7a5 (Slc7a5), plays a crucial role in amino acid sensing and signaling in specific cell types. We previously demonstrated the pivotal role of LAT1 on bone homeostasis in mice, and the expression of LAT1/SLC7A5 in vertebral cartilage of pediatric scoliosis patients; however, its role in chondrocytes on spinal homeostasis and implications regarding the underlying mechanisms during the onset and progression of scoliosis, remain unknown. Here, we identified LAT1 in mouse chondrocytes as an important regulator of postnatal spinal homeostasis. Conditional inactivation of LAT1 in chondrocytes resulted in a postnatal-onset severe thoracic scoliosis at the early adolescent stage with normal embryonic spinal development. Histological analyses revealed that Slc7a5 deletion in chondrocytes led to general disorganization of chondrocytes in the vertebral growth plate, along with an increase in apoptosis and a decrease in cell proliferation. Furthermore, loss of Slc7a5 in chondrocytes activated the general amino acid control (GAAC) pathway but inactivated the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the vertebrae. The spinal deformity in Slc7a5-deficient mice was corrected by genetic inactivation of the GAAC pathway, but not by genetic activation of the mTORC1 pathway. These findings suggest that the LAT1-GAAC pathway in chondrocytes plays a critical role in the maintenance of proper spinal homeostasis by modulating cell proliferation and survivability.
摘要：
脊柱侧弯,通常在童年和青春期早期被诊断，是脊柱的异常横向弯曲。L型氨基酸转运蛋白1(LAT1),由溶质载体转运蛋白7a5（Slc7a5）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。我们先前证明了LAT1对小鼠骨稳态的关键作用，LAT1/SLC7A5在儿童脊柱侧凸患者椎体软骨中的表达;它在软骨细胞对脊柱内稳态的作用，以及脊柱侧凸发作和进展过程中潜在机制的影响，仍然未知。这里,我们将小鼠软骨细胞中的LAT1确定为出生后脊髓稳态的重要调节因子.软骨细胞中LAT1的条件性失活导致青春期早期出生后出现严重的胸部脊柱侧弯，胚胎脊柱发育正常。组织学分析显示，软骨细胞中Slc7a5缺失导致椎体生长板中的软骨细胞普遍解体，随着细胞凋亡的增加和细胞增殖的减少。此外，软骨细胞中Slc7a5的缺失激活了一般氨基酸控制（GAAC）途径，但使椎骨中雷帕霉素复合物1（mTORC1）途径的机制靶标失活。Slc7a5缺陷小鼠的脊柱畸形通过GAAC通路的遗传失活得到纠正，但不是通过mTORC1途径的遗传激活。这些发现表明，软骨细胞中的LAT1-GAAC途径通过调节细胞增殖和生存能力在维持适当的脊髓稳态中起关键作用。
