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- Title
The L-type amino acid transporter LAT1 inhibits osteoclastogenesis and maintains bone homeostasis through the mTORC1 pathway.
- Authors
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
- Abstract
LAT1 maintains bone density: Amino acids stimulate signaling through the mammalian target of rapamycin complex 1 (mTORC1). Both amino acids and mTORC1 signaling are important for bone homeostasis. Ozaki et al. found that the expression of Slc7a5, which encodes the amino acid transporter LAT1, was reduced in osteoclast precursors in a mouse model of postmenopausal osteoporosis. Mice lacking LAT1 in osteoclasts exhibited a reduction in bone mass due to the excessive differentiation and activity of these cells. In vitro experiments using osteoclasts derived from mutant mice demonstrated that LAT1-dependent signaling through mTORC1 repressed both the transcription and nuclear accumulation of the transcription factor and master regulator of osteoclast function NFATc1 through the NF-κB and Akt signaling pathways, respectively. These findings identify a molecular mechanism through which amino acids influence bone homeostasis. 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.
- Subjects
BONE resorption; OSTEOCLASTOGENESIS; OSTEOCLASTS; AMINO acids; BONE density; HOMEOSTASIS; BONES; OSTEOPOROSIS in women
- Publication
Science Signaling, 2019, Vol 12, Issue 589, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aaw3921