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J Bone Miner Res. 2018 Oct 22. doi: 10.1002/jbmr.3609. [Epub ahead of print]

PiT1/Slc20a1 is required for endoplasmic reticulum homeostasis, chondrocyte survival and skeletal development.

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INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes, F-44042, France.
Université de Nantes, UFR Odontologie, Nantes, F-44042, France.
Baylor College of Medicine, Dept. of Molecular and Human Genetics and Orthopedic Surgery, One Baylor Plaza, Houston, Texas 77030, USA.
INSERM UMR 1132, Centre Viggo Petersen-Hôpital Lariboisière, Paris, F-75010, France.
Université Paris Diderot, Sorbonne Paris-Cité, Paris, F-75010, France.
CNRS, UMR 7365, IMoPA, Vandœuvre-lès-Nancy, F-54505, France.
Université de Lorraine, Faculté de Médecine, Vandœuvre-lès-Nancy, F-54505, France.
CHU Nantes, PHU 4 OTONN, Nantes, F-44042, France.


During skeletal mineralization, the sodium-phosphate co-transporter PiT1Slc20a1 is assumed to meet the phosphate requirements of bone-forming cells, although evidence is missing. Here, we used a conditional gene deletion approach to determine the role of PiT1 in growth plate chondrocytes. We show that PiT1 ablation shortly after birth generates a rapid and massive cell death in the center of the growth plate, together with an uncompensated ER stress, characterized by morphological changes and increased Chop, Atf4 and Bip expression. PiT1 expression in chondrocytes was not found at the cell membrane but co-localized with the ER marker ERp46, and was up-regulated by the unfolded protein response cascade. In addition, we identified the protein disulfide isomerase (Pdi) ER chaperone as a PiT1 binding partner and showed that PiT1 ablation impaired Pdi reductase activity. The ER stress induced by PiT1 deficiency in chondrocytes was associated with intracellular retention of aggrecan and Vegf-A, which was rescued by over-expressing a phosphate transport-deficient mutant of PiT1. Our data thus reveal a novel, Pi-transport independent function of PiT1, as a critical modulator of ER homeostasis and chondrocyte survival during endochondral ossification. This article is protected by copyright. All rights reserved.


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