Ablation of Enpp6 results in transient bone hypomineralization
Abstract
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.
Citation
Dillon , S , Suchacki , K , Hsu , S-N , Stephen , L A , Wang , R , Cawthorn , W P , Stewart , A J , Nudelman , F , Morton , N M & Farquharson , C 2021 , ' Ablation of Enpp6 results in transient bone hypomineralization ' , JBMR Plus , vol. 5 , no. 2 , e10439 . https://doi.org/10.1002/jbm4.10439
Publication
JBMR Plus
Status
Peer reviewed
ISSN
2473-4039Type
Journal article
Rights
Copyright © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
Description
C.F. was supported by the Biotechnology and Biological Sciences Research Council (BBSRC) via an Institute Strategic Programme Grant Funding (BB/J004316/1). S.D. was supported through a BBSRC EASTBIO Doctoral Training Partnership studentship award (1803936) and N.M.M. was supported by a Wellcome Trust New Investigator Award (100981/Z/13/Z). S.D. wrote the manuscript. S.D., K.S., S-N.H., and L.A.S. carried out experimental work. W.P.C., R.W. and N.M.M. provided reagents and materials. A.J.S., F.N. and C.F. contributed to conceptualization of the study and experimental design. All authors reviewed and edited the manuscript and approved the final version. All authors state that they have no conflicts of interest.Collections
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