A specialized metabolic pathway partitions citrate in hydroxyapatite to impact mineralization of bones and teeth

Naomi Dirckx, Qian Zhang, Emily Y. Chu, Robert J. Tower, Zhu Li, Shenghao Guo, Shichen Yuan, Pratik A. Khare, Cissy Zhang, Angela Verardo, Lucy O. Alejandro, Angelina Park, Marie Claude Faugere, Stephen L. Helfand, Martha J. Somerman, Ryan C. Riddle, Rafael de Cabo, Anne Le, Klaus Schmidt-Rohr, Thomas L. Clemens

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Citrate is a critical metabolic substrate and key regulator of energy metabolism in mammalian cells. It has been known for decades that the skeleton contains most (>85%) of the body’s citrate, but the question of why and how this metabolite should be partitioned in bone has received singularly little attention. Here, we show that osteoblasts use a specialized metabolic pathway to regulate uptake, endogenous production, and the deposition of citrate into bone. Osteoblasts express high levels of the membranous Na+-dependent citrate transporter solute carrier family 13 member 5 (Slc13a5) gene. Inhibition or genetic disruption of Slc13a5 reduced osteogenic citrate uptake and disrupted mineral nodule formation. Bones from mice lacking Slc13a5 globally, or selectively in osteoblasts, showed equivalent reductions in cortical thickness, with similarly compromised mechanical strength. Surprisingly, citrate content in mineral from Slc13a52/2 osteoblasts was increased fourfold relative to controls, suggesting the engagement of compensatory mechanisms to augment endogenous citrate production. Indeed, through the coordinated functioning of the apical membrane citrate transporter SLC13A5 and a mitochondrial zinc transporter protein (ZIP1; encoded by Slc39a1), a mediator of citrate efflux from the tricarboxylic acid cycle, SLC13A5 mediates citrate entry from blood and its activity exerts homeostatic control of cytoplasmic citrate. Intriguingly, Slc13a5-deficient mice also exhibited defective tooth enamel and dentin formation, a clinical feature, which we show is recapitulated in primary teeth from children with SLC13A5 mutations. Together, our results reveal the components of an osteoblast metabolic pathway, which affects bone strength by regulating citrate deposition into mineral hydroxyapatite.

Original languageEnglish
Article numbere2212178119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number45
DOIs
StatePublished - Nov 8 2022

Bibliographical note

Publisher Copyright:
Copyright © 2022 the Author(s).

Keywords

  • citrate
  • metabolism
  • mineralization
  • osteoblasts
  • Slc13a5

ASJC Scopus subject areas

  • General

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