The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP
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.
Szeri, Flóra; Lundkvist, Stefan; Donnelly, Sylvia; Engelke, Udo F H; Rhee, Kyu; Williams, Charlene J; Sundberg, John P; Wevers, Ron A; Tomlinson, Ryan; Jansen, Robert S; and van de Wetering, Koen, "The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP" (2020). Department of Dermatology and Cutaneous Biology Faculty Papers. Paper 133.
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This article is the author’s final published version in [Journal], Volume 16, Issue 7, July 2020, Page e1008884.
The published version is available at https://doi.org/10.1371/journal.pgen.1008884. Copyright © Szeri et al.