Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation.
OBJECTIVE
The goal of this research was to define the cellular mechanisms involved in myxomatous mitral valve disease and calcific aortic valve disease and to redefine the term degenerative valve disease in terms of an active cellular biology.


BACKGROUND
"Degenerative" valvular heart disease is the primary cause of regurgitant and stenotic valvular lesion in the U.S. However, the signaling pathways are not known. We hypothesize that valve degeneration occurs due to an osteoblastic differentiation process mediated by the low-density lipoprotein receptor-related protein 5 (Lrp5) signaling pathway to cause valve thickening.


METHODS
We examined human diseased valves: myxomatous mitral valves (n = 23), calcified tricuspid aortic valves (n = 27), calcified bicuspid aortic valves (n = 23), and control tissue from mitral and aortic valves (n = 40). The valves were examined by reverse transcriptase-polymerase chain reaction, Western blot, and immunohistochemistry for signaling markers important in osteoblast differentiation: Sox9 and Cbfa1 (transcription factors for osteoblast differentiation); Lrp5 and Wnt3 (osteoblast differentiation signaling marker), osteopontin and osteocalcin (osteoblast endochrondral bone matrix proteins), and proliferating cell nuclear antigen (a marker of cell proliferation). Cartilage development and bone formation was measured by Alcian blue stain and Alizarin red stain. Computed Scano MicroCT-40 (Bassersdorf, Switzerland) analysis measured calcium burden.


RESULTS
Low-density lipoprotein receptor-related protein 5, osteocalcin, and other osteochrondrogenic differentiation markers were increased in the calcified aortic valves by protein and gene expression (p > 0.001). Sox9, Lrp5 receptor, and osteocalcin were increased in myxomatous mitral valves by protein and gene expression (p > 0.001). MicroCT was positive in the calcified aortic valves and negative in the myxomatous mitral valves.


CONCLUSIONS
The mechanism of valvular heart disease involves an endochondral bone process that is expressed as cartilage in the mitral valves and bone in the aortic valves. Up-regulation of the Lrp5 pathway may play a role in the mechanism for valvular heart disease.
Caira
Frank C
FC
Division of Cardiology and Cardiothoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Stock
Stuart R
SR
Gleason
Thomas G
TG
McGee
Edwin C
EC
Huang
Jie
J
Bonow
Robert O
RO
Spelsberg
Thomas C
TC
McCarthy
Patrick M
PM
Rahimtoola
Shahbudin H
SH
Rajamannan
Nalini M
NM
D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve; D015153:Blotting, Western; D001857:Bone Matrix / Q000254:growth & development; D002114:Calcinosis / Q000378:metabolism / Q000503:physiopathology*; D002356:Cartilage / Q000254:growth & development; D016022:Case-Control Studies; D005260:Female; D006338:Heart Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D006349:Heart Valve Diseases / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D008875:Middle Aged; D008943:Mitral Valve; D009232:Myxoma / Q000378:metabolism / Q000503:physiopathology*; D010012:Osteogenesis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013194:Staining and Labeling; D014057:Tomography, X-Ray Computed; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D018809:Proliferating Cell Nuclear Antigen; C555507:WNT3 protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein