The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway

Kakeru Ozaki (Lead / Corresponding author), Takanori Yamada, Tetsuhiro Horie, Atsushi Ishizaki, Manami Hiraiwa, Takashi Iezaki, Gyujin Park, Kazuya Fukasawa, Hikari Kamada, Kazuya Tokumura, Mei Motono, Katsuyuki Kaneda, Kazuma Ogawa, Hiroki Ochi, Shingo Sato, Yasuhiro Kobayashi, Yun-Bo Shi, Peter M. Taylor, Eiichi Hinoi

Research output: Contribution to journalArticle

Abstract

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 κB pathway and the Akt-glycogen synthase kinase 3β 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.

Original languageEnglish
Article numberaaw3921
Pages (from-to)1-14
Number of pages14
JournalScience Signaling
Volume12
Issue number589
DOIs
Publication statusPublished - 9 Jul 2019

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Amino Acid Transport Systems
Osteoclasts
Osteogenesis
Bone
Homeostasis
Bone and Bones
Chemical activation
Amino Acids
NFATC Transcription Factors
Glycogen Synthase Kinase 3
Ovariectomy
Bone Resorption
mechanistic target of rapamycin complex 1
Nervous System Diseases
Osteoporosis
Health
Substrates

Cite this

Ozaki, K., Yamada, T., Horie, T., Ishizaki, A., Hiraiwa, M., Iezaki, T., ... Hinoi, E. (2019). The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway. Science Signaling, 12(589), 1-14. [aaw3921]. https://doi.org/10.1126/scisignal.aaw3921
Ozaki, Kakeru ; Yamada, Takanori ; Horie, Tetsuhiro ; Ishizaki, Atsushi ; Hiraiwa, Manami ; Iezaki, Takashi ; Park, Gyujin ; Fukasawa, Kazuya ; Kamada, Hikari ; Tokumura, Kazuya ; Motono, Mei ; Kaneda, Katsuyuki ; Ogawa, Kazuma ; Ochi, Hiroki ; Sato, Shingo ; Kobayashi, Yasuhiro ; Shi, Yun-Bo ; Taylor, Peter M. ; Hinoi, Eiichi. / The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway. In: Science Signaling. 2019 ; Vol. 12, No. 589. pp. 1-14.
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abstract = "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 κB pathway and the Akt-glycogen synthase kinase 3β 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.",
author = "Kakeru Ozaki and Takanori Yamada and Tetsuhiro Horie and Atsushi Ishizaki and Manami Hiraiwa and Takashi Iezaki and Gyujin Park and Kazuya Fukasawa and Hikari Kamada and Kazuya Tokumura and Mei Motono and Katsuyuki Kaneda and Kazuma Ogawa and Hiroki Ochi and Shingo Sato and Yasuhiro Kobayashi and Yun-Bo Shi and Taylor, {Peter M.} and Eiichi Hinoi",
note = "Funding: This work was supported, in part, by the Japan Society for the Promotion of Science (16H05131, 17KT0051, and 18H04971 to E.H.) and the Japan Agency for Medical Research and Development (17824969 to E.H.).",
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Ozaki, K, Yamada, T, Horie, T, Ishizaki, A, Hiraiwa, M, Iezaki, T, Park, G, Fukasawa, K, Kamada, H, Tokumura, K, Motono, M, Kaneda, K, Ogawa, K, Ochi, H, Sato, S, Kobayashi, Y, Shi, Y-B, Taylor, PM & Hinoi, E 2019, 'The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway', Science Signaling, vol. 12, no. 589, aaw3921, pp. 1-14. https://doi.org/10.1126/scisignal.aaw3921

The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway. / Ozaki, Kakeru (Lead / Corresponding author); Yamada, Takanori; Horie, Tetsuhiro; Ishizaki, Atsushi; Hiraiwa, Manami; Iezaki, Takashi; Park, Gyujin; Fukasawa, Kazuya; Kamada, Hikari; Tokumura, Kazuya; Motono, Mei; Kaneda, Katsuyuki; Ogawa, Kazuma; Ochi, Hiroki; Sato, Shingo; Kobayashi, Yasuhiro; Shi, Yun-Bo; Taylor, Peter M.; Hinoi, Eiichi.

In: Science Signaling, Vol. 12, No. 589, aaw3921, 09.07.2019, p. 1-14.

Research output: Contribution to journalArticle

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T1 - The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway

AU - Ozaki, Kakeru

AU - Yamada, Takanori

AU - Horie, Tetsuhiro

AU - Ishizaki, Atsushi

AU - Hiraiwa, Manami

AU - Iezaki, Takashi

AU - Park, Gyujin

AU - Fukasawa, Kazuya

AU - Kamada, Hikari

AU - Tokumura, Kazuya

AU - Motono, Mei

AU - Kaneda, Katsuyuki

AU - Ogawa, Kazuma

AU - Ochi, Hiroki

AU - Sato, Shingo

AU - Kobayashi, Yasuhiro

AU - Shi, Yun-Bo

AU - Taylor, Peter M.

AU - Hinoi, Eiichi

N1 - Funding: This work was supported, in part, by the Japan Society for the Promotion of Science (16H05131, 17KT0051, and 18H04971 to E.H.) and the Japan Agency for Medical Research and Development (17824969 to E.H.).

PY - 2019/7/9

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N2 - 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 κB pathway and the Akt-glycogen synthase kinase 3β 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.

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