Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification.
OBJECTIVE
- Recent studies have suggested that valvular calcification in calcific aortic stenosis (AS) may be actively regulated. "Receptor Activator of Nuclear factor kappaB Ligand" (RANKL) and osteoprotegerin (OPG) are members of a cytokine system involved in bone turnover and vascular calcification. Their role in calcific AS is not known.


RESULTS
- By immunohistochemistry using human aortic valves, RANKL was not expressed at relevant levels in controls but detectable in AS. OPG expression was marked in controls but significantly lower in AS. Areas containing focal calcification exhibited significantly less OPG-positive cells as compared to non-calcified regions. Stimulation with RANKL lead to a significant rise in matrix calcification, nodule formation, alkaline phosphatase activity, expression of the bone-type isoenzyme of alkaline phosphatase, and expression of osteocalcin in cultured human aortic valve myofibroblasts. Moreover, RANKL increased DNA binding of the essential osteoblast transcription factor cbfa-1.


CONCLUSIONS
- RANKL and OPG are differentially expressed in calcific AS. In cultured human aortic valve myofibroblasts, RANKL promotes matrix calcification and induces the expression of osteoblast-associated genes, indicating a transition towards an osteogenic phenotype. These results suggest that the RANKL-OPG pathway may regulate valvular calcification in calcific AS?
Kaden
Jens J
JJ
First Department of Medicine (Cardiology, Angiology, and Pneumology), Faculty of Clinical Medicine Mannheim, University of Heidelberg, Theordor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. jens.kaden@med.ma.uni-heidelberg.de
Bickelhaupt
Svetlana
S
Grobholz
Rainer
R
Haase
Karl K
KK
Sarikoç
Aslihan
A
Kiliç
Refika
R
Brueckmann
Martina
M
Lang
Siegfried
S
Zahn
Ingrid
I
Vahl
Christian
C
Hagl
Siegfried
S
Dempfle
Carl Erik
CE
Borggrefe
Martin
M
D001021:Aortic Valve / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D005347:Fibroblasts; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D053244:Osteoprotegerin; D011485:Protein Binding / Q000187:drug effects; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D012598:Sclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D053244:Osteoprotegerin; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D004247:DNA