Title | The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Szeri F, Lundkvist S, Donnelly S, Engelke UFH, Rhee K, Williams CJ, Sundberg JP, Wevers RA, Tomlinson RE, Jansen RS, van de Wetering K |
Journal | PLoS Genet |
Volume | 16 |
Issue | 7 |
Pagination | e1008884 |
Date Published | 2020 07 |
ISSN | 1553-7404 |
Keywords | Adenosine Triphosphate, Animals, Bone and Bones, Bone Development, Calcinosis, Cell Differentiation, Cells, Cultured, Citric Acid, Diphosphates, Humans, Mechanical Phenomena, Mice, Mutation, Phosphate Transport Proteins |
Abstract | The membrane protein ANKH was known to prevent pathological mineralization of joints and was thought to export pyrophosphate (PPi) from cells. This did not explain, however, the presence of ANKH in tissues, such as brain, blood vessels and muscle. We now report that in cultured cells ANKH exports ATP, rather than PPi, and, unexpectedly, also citrate as a prominent metabolite. The extracellular ATP is rapidly converted into PPi, explaining the role of ANKH in preventing ankylosis. Mice lacking functional Ank (Ankank/ank mice) had plasma citrate concentrations that were 65% lower than those detected in wild type control animals. Consequently, citrate excretion via the urine was substantially reduced in Ankank/ank mice. Citrate was even undetectable in the urine of a human patient lacking functional ANKH. The hydroxyapatite of Ankank/ank mice contained dramatically reduced levels of both, citrate and PPi and displayed diminished strength. Our results show that ANKH is a critical contributor to extracellular citrate and PPi homeostasis and profoundly affects bone matrix composition and, consequently, bone quality. |
DOI | 10.1371/journal.pgen.1008884 |
Alternate Journal | PLoS Genet |
PubMed ID | 32639996 |
PubMed Central ID | PMC7371198 |
Grant List | R01 AR072695 / AR / NIAMS NIH HHS / United States |