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bioRxiv · 10.1101/2019.12.20.883223

Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance

Szeri, F.·Lundkvist, S.·Donnelly, S.·Engelke, U. F. H.·Rhee, K.·Williams, C.·Sundberg, J. P.·Wevers, R. A.·Tomlinson, R. E.·Jansen, R. S.·van de Wetering, K.
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Abstract

The membrane protein Ankylosis homologue (ANKH, mouse orthologue: ANK) prevents mineralization of joint-space and articular cartilage. The accepted view is that ANKH mediates cellular release of inorganic pyrophosphate (PPi), a strong physiological inhibitor of mineralization. Using global metabolite profiling, we identified citrate as the most prominent metabolite leaving HEK293 cells in an ANKH-dependent manner. Although PPi levels were increased in culture medium of HEK293-ANKH cells, PPi was formed extracellularly after release of ATP and other nucleoside triphosphates. Ankank/ank mice, which lack functional ANK, had substantially reduced concentrations of citrate in plasma and urine, while citrate was undetectable in urine of a human patient lacking functional ANKH. Bone hydroxyapatite of Ankank/ank mice also contained markedly reduced levels of citrate and PPi and displayed diminished strength. Together, our data show that ANKH is a crucial factor in extracellular citrate and PPi homeostasis that is essential for normal bone development.

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Szeri, F., Lundkvist, S., Donnelly, S., Engelke, U. F. H., Rhee, K., Williams, C., Sundberg, J. P., Wevers, R. A., Tomlinson, R. E., Jansen, R. S., van de Wetering, K.. 2019-12-20. Ankylosis homologue (ANKH) controls extracellular citrate and pyrophosphate homeostasis and affects bone mechanical performance. https://doi.org/10.1101/2019.12.20.883223

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