Publikationsdatum:
2019
Beschreibung:
〈p〉L-type amino acid transporter 1 (LAT1), which is encoded by 〈i〉solute carrier transporter 7a5〈/i〉 (〈i〉Slc7a5〈/i〉), 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. 〈i〉Slc7a5〈/i〉 expression was substantially reduced in osteoclasts in a mouse model of ovariectomy-induced osteoporosis. The osteoclast-specific deletion of 〈i〉Slc7a5〈/i〉 in mice led to osteoclast activation and bone loss in vivo, and 〈i〉Slc7a5〈/i〉 deficiency increased osteoclastogenesis in vitro. Loss of 〈i〉Slc7a5〈/i〉 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 〈i〉Slc7a5〈/i〉-deficient mice. Last, 〈i〉Slc7a5〈/i〉 deficiency increased the expression of nuclear factor of activated T cells, cytoplasmic 1 (〈i〉Nfatc1〈/i〉) and the nuclear accumulation of NFATc1, a master regulator of osteoclast function, possibly through the canonical nuclear factor B 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.〈/p〉
Print ISSN:
1945-0877
Digitale ISSN:
1937-9145
Thema:
Biologie
,
Medizin
