Noncollagenous bone matrix proteins as a part of calcific aortic valve disease regulation.
Clinically, calcific aortic valve disease is a progressive continuum from obstructive fibro(sclero)tic valve thickening to aortic stenosis. Recent evidence suggests that, in addition to nonbone miscellaneous mineralization, calcified valves present distinct signs of active bone remodeling; and in this context, noncollagenous bone-associated proteins are assumed to have a critical role. The expression of 5 bone matrix proteins-bone morphogenetic protein-2 and -4, bone sialoprotein II, osteopontin, and osteoprotegerin-was examined by reverse transcriptase polymerase chain reaction (n = 31) and immunolabeling (n = 83) in the clinical continuum from healthy pliable valves to heavily calcified ones. As a known structural pathologic sign, the extent of neovascularization was also examined. We observed progressive increase in the gene expression of osteopontin (7.4-fold elevation, P < .001) and bone sialoprotein II (5.8-fold elevation, P < .05), and also 1.7-fold elevation (P < .05) in osteoprotegerin gene expression during the disease course. These findings were congruent with that of immunohistochemical analysis. Surprisingly, bone morphogenetic protein-2 and -4 showed a comparable significant decrease in messenger RNA levels in calcified valves (P < .01 and P < .05, respectively). Our results support the view that aortic valve calcification is an actively regulated process. Furthermore, the results suggest that the expression of pro- and anticalcific noncollagenous bone-associated matrix proteins is altered during the disease continuum and that this imbalance may contribute to the pathology of calcific aortic valve disease.
Pohjolainen
Virva
V
Department of Pharmacology and Toxicology, University of Oulu, Oulu, Finland.
Taskinen
Panu
P
Soini
Ylermi
Y
Rysä
Jaana
J
Ilves
Mika
M
Juvonen
Tatu
T
Ruskoaho
Heikki
H
Leskinen
Hanna
H
Satta
Jari
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000378:metabolism*; D001024:Aortic Valve Stenosis / Q000473:pathology*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002114:Calcinosis / Q000473:pathology*; D009202:Cardiomyopathies / Q000473:pathology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D058574:Integrin-Binding Sialoprotein; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D053495:Osteopontin / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D053244:Osteoprotegerin; D012795:Sialoglycoproteins; D053495:Osteopontin