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Localization of Osteoprotegerin, Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand, and Receptor Activator of Nuclear Factor-B Ligand in Mönckeberg’s Sclerosis and Atherosclerosis

Departments of Internal Medicine and Cardiology (M.S., B.M.), Gastroenterology, Endocrinology and Metabolism (L.C.H.), and Pathology (P.J.B.), Philipps University, D-35033 Marburg, Germany; and Departments of Clinical Chemistry (N.A.-F., N.K.), Pathology (F.E.F.), and Biochemistry (K.T.P.), Justus Liebig University, D-35390 Giessen, Germany

Address all correspondence and requests for reprints to: Dr. Michael Schoppet, Department of Internal Medicine and Cardiology, Philipps University, Baldingerstrasse, D-35033 Marburg, Germany. E-mail: schoppet{at}mailer.uni-marburg.de.

Vascular calcification may occur at different areas of the vessel wall, including the intima in atherosclerosis and the media in Mönckeberg’s sclerosis. Medial calcification of arteries is common in patients with diabetes mellitus or chronic renal failure. Osteoprotegerin (OPG) and receptor activator of nuclear factor-B ligand are essential modulators of bone homeostasis and may be involved in the process of vascular calcification. In this study we investigated arteries from patients with Mönckeberg’s sclerosis and atherosclerosis. Apoptosis, which precedes vascular calcification in vitro, was assessed by an in situ ligation assay and was localized to the medial layer of arteries (Mönckeberg’s sclerosis) and the neointima (atherosclerosis). Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Mönckeberg’s sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis). Receptor activator of nuclear factor-B ligand protein and mRNA were barely or not detectable. Of note, TNF-related apoptosis-inducing ligand, an inducer of apoptosis that is also blocked by OPG, displayed a similar spatial distribution as OPG. In summary, we demonstrate enhanced apoptosis adjacent to vascular calcification, and the concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG, suggesting their involvement in the pathogenesis of vascular calcification.

This work was supported by a Heisenberg fellowship from the Deutsche Forschungsgemeinschaft (to L.C.H.; Ho 1875/3-1 and Ho 1875/4-1).

M.S. and N.A.-F. contributed equally to this work.

Abbreviations: DIG, Digoxigenin; DNase, deoxyribonuclease; EC, endothelial cells; ISL, in situ ligation assay; NBT/BCIP, nitro blue tetrazolium/5-bromo-4-chloro-3-indolyl-phosphate; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-B; RANKL, RANK ligand; RNase, ribonuclease; SSC, sodium citrate buffer; TRAIL, TNF-related apoptosis-inducing ligand; VSMC, vascular smooth muscle cells.

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