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J. Cardiovasc. Dev. Dis. 2015, 2(2), 31-47; doi:10.3390/jcdd2020031

N-acetylglucosamine-1-Phosphate Transferase Suppresses Lysosomal Hydrolases in Dysfunctional Osteoclasts: A Potential Mechanism for Vascular Calcification

Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Academic Editors: Cheryl L. Maslen and Russell Norris
Received: 21 February 2015 / Revised: 31 March 2015 / Accepted: 7 April 2015 / Published: 15 April 2015
(This article belongs to the Special Issue Genetics and Cardiovascular Development and Disease)
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Abstract

In addition to increased differentiation of vascular smooth muscle cells into osteoblast-like phenotypes, the limited accumulation of osteoclasts in atherosclerotic plaques or their dysfunction may participate in potential mechanisms for vascular calcification. N-acetylglucosamine-1-phosphate transferase containing alpha and beta subunits (GNPTAB) is a transmembrane enzyme complex that mediates the vesicular transport of lysosomal hydrolases. GNPTAB may also regulate the biogenesis of lysosomal hydrolases from bone-marrow derived osteoclasts. In this study, the areas surrounding calcification in human atherosclerotic plaques contained high levels of GNPTAB and low levels of lysosomal hydrolases such as cathepsin K (CTSK) and tartrate-resistant acid phosphatase (TRAP), as demonstrated by immunohistochemistry and laser-capture microdissection-assisted mRNA expression analysis. We therefore hypothesized that GNPTAB secretion may suppress the release of CTSK and TRAP by vascular osteoclast-like cells, thus causing their dysfunction and reducing the resorption of calcification. We used human primary macrophages derived from peripheral blood mononuclear cells, an established osteoclast differentiation model. GNPTAB siRNA silencing accelerated the formation of functional osteoclasts as detected by increased secretion of CTSK and TRAP and increased their bone resorption activity as gauged by resorption pits assay. We concluded that high levels of GNPTAB inhibit secretion of lysosomal hydrolases in dysfunctional osteoclasts, thereby affecting their resorption potential in cardiovascular calcification. View Full-Text
Keywords: GNPTAB; vascular calcification; osteoclast; lysosomal hydrolases GNPTAB; vascular calcification; osteoclast; lysosomal hydrolases
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Lei, Y.; Iwashita, M.; Choi, J.; Aikawa, M.; Aikawa, E. N-acetylglucosamine-1-Phosphate Transferase Suppresses Lysosomal Hydrolases in Dysfunctional Osteoclasts: A Potential Mechanism for Vascular Calcification. J. Cardiovasc. Dev. Dis. 2015, 2, 31-47.

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J. Cardiovasc. Dev. Dis. EISSN 2308-3425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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