Expression of bone sialoprotein and bone morphogenetic protein-2 in calcific aortic stenosis.
OBJECTIVE
Calcific aortic stenosis, the major heart valve disease encountered in the elderly, leads to massive calcium deposition in the valve leaflets that morphologically resembles bone formation. Recent studies have demonstrated the expression of various bone-associated proteins in stenotic valves, suggesting that valvular calcification may be an actively regulated process. Bone sialoprotein (BSP), a non-collagenous bone matrix protein, and bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor cytokine superfamily, are known to participate in the regulation of bone development and maturation. Their pathogenetic role in calcific aortic stenosis is unknown.


METHODS
Using an immunoperoxidase technique and antibodies against BSP and BMP-2, the expression of BSP and BMP-2 was examined in 16 human aortic valves with calcific aortic stenosis obtained at valve replacement, and in seven normal autopsy controls without signs of aortic stenosis.


RESULTS
By semiquantitative scoring, stenotic valves showed a significantly increased staining of BSP in cells and extracellular matrix as compared to control valves (2.7 +/- 0.1 versus 0.6 +/- 0.2 score units, p <0.001). Marked BMP-2 expression was detected in stenotic valves, mostly in cell-rich areas associated with focal calcium deposits, but no specific staining for BMP-2 was detected in control valves (1.5 +/- 0.2 versus 0.0 +/- 0.0 score units, p <0.001).


CONCLUSIONS
These results demonstrate for the first time that BSP and BMP-2 are differentially expressed in normal aortic valves and in aortic stenosis, thereby supporting the concept that valvular calcification might be based on an actively regulated process involving BSP and BMP-2.
1st Department of Medicine (Cardiology, Angiology, and Pneumology), University Hospital of Mannheim, Germany. jens.kaden@med.ma.uni-heidelberg.de
Jens J
JJ
Kaden
Svetlana
S
Bickelhaupt
Rainer
R
Grobholz
Christian F
CF
Vahl
Siegfried
S
Hagl
Martina
M
Brueckmann
Karl K
KK
Haase
Carl-Erik
CE
Dempfle
Martin
M
Borggrefe
D000368:Aged; D001021:Aortic Valve / Q000378:metabolism / Q000473:pathology; D001024:Aortic Valve Stenosis / Q000378:metabolism*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis*; D002114:Calcinosis / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D058574:Integrin-Binding Sialoprotein; D008297:Male; D012795:Sialoglycoproteins / Q000096:biosynthesis*; D013194:Staining and Labeling; D013223:Statistics as Topic; D016212:Transforming Growth Factor beta
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D002118:Calcium