Amino acid signaling is critical to maintain proper posture!
-Development of a new treatment method for scoliosis-

最新研究成果(最終英語版)大学HP用.jpg

Scoliosis is defined as the sideways curvature of the spine that causes a trunk deformity. Most cases of scoliosis are idiopathic, i.e., of unknown origin. Of these, adolescent idiopathic scoliosis is the most common condition that mostly affects girls during puberty. This disease can become self-limiting when trunk deformity worsens. Such cases require deformity correction or surgery. Thus, it is desirable to identify the etiology of adolescent idiopathic scoliosis and establish effective treatment methods for it.

Amino acids are nutrients that passively serve as substrates for protein synthesis and actively act as signaling molecules. The intracellular influx of amino acids through amino acid transporters is essential for initiating amino acid signaling. L-type amino acid transporter 1 (LAT1), encoded by Slc7a5, can transport large neutral amino acids, including leucine and isoleucine.

On analysis of pathological specimen, a research group determined that the expression of LAT1 differs in the cartilaginous tissues of the spinous process in patients with congenital scoliosis and idiopathic scoliosis. They proposed that amino acid signaling is involved in the maintenance of spinal homeostasis (Demura et al., Spine Surg. Relat. Res. 2021).

This study revealed that inactivation of LAT1, an amino acid transporter, resulted in the deformity of cartilaginous tissues, leading to the onset of scoliosis-like symptoms. Furthermore, it demonstrated that amino acid signaling played an important role in the "maintenance of spinal homeostasis." The results of this study are expected to act as a basis to elucidate the etiology of idiopathic scoliosis and establish novel diagnostic and treatment procedures for it.

Points of this study

  • Adolescent idiopathic scoliosis is a common disease that affects 2%-3% of the Japanese population. Understanding its etiology and establishing new diagnostic and treatment procedures for this disease is crucial.
  • Inactivation of LAT1, an amino acid transporter, leads to a breakdown in the homeostasis of cartilaginous tissues, thus resulting in the onset of scoliosis-like symptoms.
  • LAT1 maintains homeostasis of cartilaginous tissues through the general amino acid control (GAAC) pathway.
  • These results indicate that the LAT1-GAAC pathway can be a new therapeutic target in patients with scoliosis.

Summary of study results

A research group revealed that LAT1 in osteoclasts plays an important role in the maintenance of bone tissue homeostasis (Ozaki K., et al., Sci. Signal. 2019). Furthermore, expression differs according to severity of scoliosis (Demura et al., Spine Surg. Relat. Res. 2021).

Initially, the research group developed a mouse model with chondrocyte-specifically inactivated
LAT1 (LAT1 knockout mice) to clarify the functional role of LAT1 in skeletal formation and
homeostasis of cartilaginous tissues. Extensive analysis of phenotypes of the LAT1 knockout mice
indicated no abnormality in the skeletal structure during the embryonic phase; however, scoliosis-like
symptoms developed 4 weeks after birth (Figure 1).

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Figure 1: LAT1 deficiency in chondrocytes causes idiopathic scoliosis.

Next, the research group performed histological analysis of the spine to determine why the inactivation of LAT1 causes scoliosis-like symptoms. The results indicated that the abnormal chondrocyte morphology and derangement in the column order of the cartilaginous growth plate of the LAT1 knockout mice were responsible (Figure 2). Further analysis revealed a decrease in cell proliferation of the prehypertrophic layer of chondrocytes and aggravated cell death in the hypertrophic layer of chondrocytes.

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Figure 2: LAT1 deficiency in chondrocytes causes general disorganization of chondrocytes in the vertebral growth plate.

Subsequently, the research group developed a time-specific LAT1 knockout mouse model and analyzed their phenotypes to determine when LAT1 plays an important role after birth. The results indicated that there was no spinal abnormality in mice with LAT1 inactivated at 4 weeks after birth. In other words, LAT1 in chondrocytes plays an important role in the maintenance of spinal homeostasis during a specific period from birth to puberty.

Finally, the research group investigated the mechanism underlying the regulation of spinal homeostasis by LAT1. Protein expression analysis revealed the activation of the GAAC pathway in cartilaginous tissues of the LAT1 knockout mice. When the group introduced Atf4 heterodeficiency into the LAT1 knockout mice (i.e., mice with inactivated GAAC pathway, i.e., generation of rescue mice), scoliosis-like symptoms in the LAT1 knockout mice remarkably attenuated (Figure 3).

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Figure 3. GAAC pathway is implicated in spinal deformity in LAT1 deficiency.

The results of this study showed that LAT1 in chondrocytes maintains spinal homeostasis by regulating cell proliferation and cell death through the GAAC pathway and plays an important role in the proper maintenance of trunk function (Figure 4).

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Figure 4. LAT1/GAAC pathway in vertebral growth plate chondrocy

Significance of this study and future viewpoints

The results of this study suggesting the importance of amino acid signaling in the maintenance of proper posture. Moreover, they provide a novel solution for several problems related to locomotor disease and bone diseases induced by a breakdown in the homeostasis of cartilaginous tissues. These results could be the solution to unmet medical needs. These findings can act as the basis for the development of a drug based on an amino acid transporter molecule to be used for the curative care for patients with scoliosis, along with the development of new diagnostic procedures assisted by nuclear medicine imaging and treatment methods using radiotheranostics.

Article information

Journal: Journal of Cellular Physiology
Article title: Conditional inactivation of the L-type amino acid transporter LAT1 in chondrocytes models idiopathic scoliosis in mice
Author list: Sayuki Iwahashi, Jiajun Lyu, Kazuya Tokumura, Ryoma Osumi, Manami Hiraiwa, Takuya Kubo, Tetsuhiro Horie, Satoru Demura, Noriaki Kawakami, Taku Saito, Gyujin Park, Kazuya Fukasawa, Takashi Iezaki, Akane Suzuki, Akane Tomizawa, Hiroki Ochi, Hironori Hojo, Shinsuke Ohba and Eiichi Hinoi.
DOI: 10.1002/jcp.30883
Lab: Laboratory of Pharmacology (https://sites.google.com/gifu-pu.ac.jp/labo-yakuri)