Osteopontin Upregulation and Polymerization by Transglutaminase 2 in Calcified Arteries of Matrix Gla Protein-deficient Mice

Mari T. Kaartinen ^1*, Monzur Murshed ¹, Gerard Karsenty ¹ and Marc D. McKee ¹

¹ Division of Biomedical Sciences, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada (MTK,MDM), and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas (MM,GK)

^* To whom correspondence should be addressed. E-mail: mari.kaartinen{at}mcgill.ca .

Submitted on September 1, 2006
Accepted on 7 December 2006

	Abstract

Matrix Gla protein (MGP) is a potent inhibitor of soft tissue calcification, and Mgp gene deletion in mice results in arterial calcification. Our aim was to examine osteopontin (OPN) expression and localization, and post-translational processing of OPN by the crosslinking enzyme transglutaminase 2 (TG2), in the calcified aorta of Mgp-deficient (Mgp^-/-) mice. Using immunohistochemistry and light and electron microscopy, we report that following the mineralization that occurs in the arterial media of Mgp^-/- aortas, OPN is upregulated and accumulates at the surface of the calcified elastic lamellae. Macrophages were observed in direct contact with this OPN-rich layer. Western blot analysis of extracted Mgp^-/- aortas revealed that the majority of the OPN was in high-molecular weight protein complexes indicating modification by a crosslinking enzyme. Consistent with this observation, TG2 expression and -glutamyl--lysyl crosslink levels were also increased in Mgp^-/- aortas. In addition to the mineral-inhibiting actions of OPN, and based on data linking OPN and TG2 with cell adhesion in various cell types including monocytes and macrophages, we propose that TG2 interactions with OPN lead to protein polymerization that facilitates macrophage adhesion to the calcified elastic lamellae to promote clearance of the ectopic mineral deposits.

Key Words: Matrix Gla protein, osteopontin, transglutaminase, artery, biomineralization, pathologic ectopic calcification, vascular calcification, macrophage, crosslinks

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