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PiT1/Slc20a1 Is Required for Endoplasmic Reticulum Homeostasis, Chondrocyte Survival, and Skeletal Development
Author(s) -
Couasnay Greig,
Bon Nina,
Devignes ClaireSophie,
Sourice Sophie,
Bianchi Arnaud,
Véziers Joëlle,
Weiss Pierre,
Elefteriou Florent,
Provot Sylvain,
Guicheux Jérôme,
BeckCormier Sarah,
Beck Laurent
Publication year - 2019
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.3609
Subject(s) - unfolded protein response , endoplasmic reticulum , chondrocyte , microbiology and biotechnology , protein disulfide isomerase , chemistry , atf4 , endocrinology , medicine , endochondral ossification , cartilage , biology , anatomy
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 endoplasmic reticulum (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 upregulated 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 vascular endothelial growth factor A (Vegf‐A), which was rescued by overexpressing 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. © 2018 American Society for Bone and Mineral Research.