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Human Degenerative Valve Disease Is Associated With Up-Regulation of Low-Density Lipoprotein Receptor-Related Protein 5 Receptor-Mediated Bone Formation

Frank C. Caira, BSc^_*, Stuart R. Stock, PhD, Thomas G. Gleason, MD^_*, Edwin C. McGee, MD^_*, Jie Huang, ScD, Robert O. Bonow, MD, FACC^_*, Thomas C. Spelsberg, PhD, Patrick M. McCarthy, MD, FACC^_*, Shahbudin H. Rahimtoola, MB, FRCP, DSc, MACC, MACP^|| and Nalini M. Rajamannan, MD, FACC^_*,a,_*

^_* Division of Cardiology and Cardiothoracic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Institute for Bioengineering and Nanoscience in Advanced Medicine, Northwestern University, Chicago, Illinois
Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois
Department of Molecular Biology and Biochemistry, Mayo Clinic College of Medicine, Rochester, Minnesota
^|| Division of Cardiovascular Medicine, Department of Medicine, LAC + USC Medical Center, Keck School of Medicine at the University of Southern California, Los Angeles, California

View larger version (88K): [in a new window]   Figure 1 Immunohistochemistry of the human mitral degenerative valves and calcified tricuspid and bicuspid aortic valves for calcification, cartilage, and MicroCT scan. Control valve, degenerative mitral valve (arrow points to hypertrophic chondrocytes), calcified aortic valves (arrow points to positive stain), and bicuspid aortic valve (arrow points to positive stain) (magnification 25x). (A) Alizarin red stain. (B) Alcian blue stain. (C) MicroCT scan (gray area is the soft tissue, white area is calcification, blue is the background).

View larger version (86K): [in a new window]   Figure 2 Immunohistochemistry of the human mitral degenerative valves and calcified tricuspid and bicuspid aortic valves for non-collagenous bone matrix synthesis. Control valve, degenerative mitral valve (arrow points to hypertrophic chondrocytes), calcified aortic valves (arrow points to positive stain), and bicuspid aortic valve (arrow points to positive stain) (magnification 25x). Insert within each photo is a high-power magnification to demonstrate cellular staining (magnification 40x). (A) Bone sialoprotein stain. (B) Osteopontin stain. (C) Osteocalcin stain.

View larger version (96K): [in a new window]   Figure 3 Immunohistochemistry of the human mitral degenerative valves and calcified tricuspid and bicuspid aortic valves for endochondral signaling markers low-density lipoprotein receptor-related protein 5/Wnt and proliferating cell nuclear antigen. Control valve, degenerative mitral valve (arrow points to hypertrophic chondrocytes), calcified aortic valves (arrow points to positive stain), and bicuspid aortic valve (arrow points to positive stain) (magnification 25x). Insert within each photo is a high-power magnification to demonstrate cellular staining (magnification 40x). (A) lipoprotein receptor-related protein 5 stain. (B) Wnt 3 stain. (C) Proliferating cell nuclear antigen stain.

View larger version (56K): [in a new window]   Figure 4 Western blot. Western blot analysis for lipoprotein receptor-related protein 5 (Lrp5), osteocalcin, ß-catenin, p42/44, and -actin.

View larger version (71K): [in a new window]   Figure 5 Semiquantitative reverse transcriptase-polymerase chain reaction. Reverse transcriptase-polymerase chain reaction results for Cbfa1, Sox9, cyclin, osteocalcin, and osteopontin.