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 AT...
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| creator | Szeri, Flora Lundkvist, Stefan Donnelly, Sylvia Engelke, Udo F H Rhee, Kyu Williams, Charlene J Sundberg, John P Wevers, Ron A Tomlinson, Ryan E Jansen, Robert S van de Wetering, Koen |
| description | 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_str_mv | 10.1371/journal.pgen.1008884 |
| format | Article |
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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.</description><identifier>ISSN: 1553-7404</identifier><identifier>ISSN: 1553-7390</identifier><identifier>EISSN: 1553-7404</identifier><identifier>DOI: 10.1371/journal.pgen.1008884</identifier><identifier>PMID: 32639996</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adenosine Triphosphate - metabolism ; Animals ; ANK protein ; ANKH protein ; Ankylosis ; ATP (Adenosine triphosphate) ; Biology ; Biology and Life Sciences ; Blood vessels ; Bone and Bones - metabolism ; Bone composition ; Bone Development - genetics ; Bone matrix ; Bone surgery ; Bones ; Calcinosis - genetics ; Calcinosis - metabolism ; Calcinosis - pathology ; Cell Differentiation ; Cells, Cultured ; Citrates ; Citric acid ; Citric Acid - metabolism ; Cloning ; Dermatology ; Diphosphates - metabolism ; Excellence ; Genetic aspects ; Health aspects ; Homeostasis ; Humans ; Hydroxyapatite ; Infectious diseases ; Laboratories ; Mechanical Phenomena ; Medical schools ; Medicine ; Medicine and Health Sciences ; Membrane proteins ; Metabolism ; Metabolites ; Mice ; Mineralization ; Musculoskeletal physiology ; Mutation - genetics ; Phosphate Transport Proteins - genetics ; Phosphate Transport Proteins - metabolism ; Physiological aspects ; Physiology ; Proteins</subject><ispartof>PLoS genetics, 2020-07, Vol.16 (7), p.e1008884-e1008884</ispartof><rights>COPYRIGHT 2020 Public Library of Science</rights><rights>2020 Szeri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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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.</description><subject>Adenosine Triphosphate - metabolism</subject><subject>Animals</subject><subject>ANK protein</subject><subject>ANKH protein</subject><subject>Ankylosis</subject><subject>ATP (Adenosine triphosphate)</subject><subject>Biology</subject><subject>Biology and Life Sciences</subject><subject>Blood vessels</subject><subject>Bone and Bones - metabolism</subject><subject>Bone composition</subject><subject>Bone Development - genetics</subject><subject>Bone matrix</subject><subject>Bone surgery</subject><subject>Bones</subject><subject>Calcinosis - genetics</subject><subject>Calcinosis - metabolism</subject><subject>Calcinosis - pathology</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Citrates</subject><subject>Citric acid</subject><subject>Citric Acid - metabolism</subject><subject>Cloning</subject><subject>Dermatology</subject><subject>Diphosphates - 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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. 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| subjects | Adenosine Triphosphate - metabolism Animals ANK protein ANKH protein Ankylosis ATP (Adenosine triphosphate) Biology Biology and Life Sciences Blood vessels Bone and Bones - metabolism Bone composition Bone Development - genetics Bone matrix Bone surgery Bones Calcinosis - genetics Calcinosis - metabolism Calcinosis - pathology Cell Differentiation Cells, Cultured Citrates Citric acid Citric Acid - metabolism Cloning Dermatology Diphosphates - metabolism Excellence Genetic aspects Health aspects Homeostasis Humans Hydroxyapatite Infectious diseases Laboratories Mechanical Phenomena Medical schools Medicine Medicine and Health Sciences Membrane proteins Metabolism Metabolites Mice Mineralization Musculoskeletal physiology Mutation - genetics Phosphate Transport Proteins - genetics Phosphate Transport Proteins - metabolism Physiological aspects Physiology Proteins |
| title | The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP |
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