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Ablation of Enpp6 results in transient bone hypomineralization

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Scott Dillon, Karla Suchacki, Shun-Neng Hsu, Louise A. Stephen, Rongling Wang, William P. Cawthorn, Alan J. Stewart, Fabio Nudelman, Nicholas M. Morton, Colin Farquharson

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Biomineralization is a fundamental process key to the development of the skeleton. The phosphatase orphan phosphatase 1 (PHOSPHO1), which likely functions within extracellular matrix vesicles, has emerged as a critical regulator of biomineralization. The biochemical pathways which generate intravesicular PHOSPHO1 substrates are however currently unknown. We hypothesized that the enzyme ectonucleotide pyrophosphatase/phosphodiesterase (ENPP6) is an upstream source of PHOSPHO1 substrate. To test this, we characterized skeletal phenotypes of mice homozygous for a targeted deletion of Enpp6 (Enpp6‒/‒). Micro-computed tomography of the trabecular compartment revealed transient hypomineralization in Enpp6‒/‒ tibiae (p < 0.05) that normalized by 12 weeks of age. Whole-bone cortical analysis also revealed significantly hypomineralized proximal bone in 4– but not 12–week old Enpp6‒/‒ mice (p < 0.05) compared to wild-type animals. Backscattered scanning electron microscopy revealed a failure in 4-week-old trabecular bone of mineralization foci to propagate. Static histomorphometry revealed increased osteoid volume (p>0.01) and osteoid surface (p < 0.05) which recovered by 12 weeks but was not accompanied by changes in osteoblast or osteoclast number. This study is the first to characterize the skeletal phenotype of Enpp6‒/‒ mice, revealing transient hypomineralization in young animals compared to wild-type controls. These data suggest that ENPP6 is important for bone mineralization and may function upstream of PHOSPHO1 as a novel means of generating its substrates inside matrix vesicles.


Original languageEnglish
Article numbere10439
Number of pages11
JournalJBMR Plus
VolumeEarly View
Early online date8 Dec 2020
Publication statusE-pub ahead of print - 8 Dec 2020

    Research areas

  • Ectonucleotide pyrophosphatase/phosphodiesterase 6, Matrix mineralization, Matrix vesicle, Orphan phosphatase 1, Osteoblast

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