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.
Highlights
Physiological mineralization is essential for normal development of vertebrates, but must be restricted to specific sites of the body
Ank homolog (ANKH) is involved in extracellular citrate and pyrophosphate homeostasis
ANKH is involved in extracellular citrate and pyrophosphate homeostasis levels of ANKH protein were found in cells overexpressing ANKHwt
Summary
Physiological mineralization is essential for normal development of vertebrates, but must be restricted to specific sites of the body. The molecular details of the mechanism in vertebrates that restrict mineralization to specific sites of the body are incompletely characterized, . A naturally occurring mouse mutant, progressive ankylosis (Ankank/ank), presents early in life with progressive ankylosis of the spine and other joints, restricting mobility and critically limiting lifespan [1]. Biallelic loss-of-function mutations in the human orthologue of Ank, Ank homolog (ANKH), result in progressive small joint soft-tissue calcification, hearing loss, progressive spondyloarthropathy and mental retardation [5], clinical manifestations very similar to those observed in Ankank/ank mice[1]. We have previously shown that ATP release mediated by the hepatic membrane protein ATP-Binding Cassette subfamily C member 6 (ABCC6) is responsible for 60–70% of all PPi present in plasma [8,9]
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