The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP


Autoři: Flora Szeri aff001;  Stefan Lundkvist aff001;  Sylvia Donnelly aff001;  Udo F. H. Engelke aff002;  Kyu Rhee aff003;  Charlene J. Williams aff004;  John P. Sundberg aff005;  Ron A. Wevers aff002;  Ryan E. Tomlinson aff006;  Robert S. Jansen aff003;  Koen van de Wetering aff001
Působiště autorů: Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Department of Dermatology and Cutaneous Biology, Jefferson Institute of Molecular Medicine and PXE International Center of Excellence in Research and Clinical Care, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, Un aff001;  Translational Metabolic Laboratory, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands aff002;  Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, New York, United States of America aff003;  Cooper Medical School of Rowan University, Camden, New Jersey, United States of America aff004;  The Jackson Laboratory, Bar Harbor, Maine, United States of America aff005;  Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America aff006
Vyšlo v časopise: The membrane protein ANKH is crucial for bone mechanical performance by mediating cellular export of citrate and ATP. PLoS Genet 16(7): e32767. doi:10.1371/journal.pgen.1008884
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008884

Souhrn

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.

Klíčová slova:

Blood plasma – Bone and joint mechanics – Bone density – Cell metabolism – Femur – Homeostasis – Membrane proteins – Urine


Zdroje

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2020 Číslo 7

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