Osteo/chondrocytic transcription factors and their target genes exhibit distinct patterns of expression in human arterial calcification.
OBJECTIVE
Mineralization-regulating proteins are found deposited at sites of vascular calcification. However, the relationship between the onset of calcification in vivo and the expression of genes encoding mineralization-regulating proteins is unknown. This study aimed to determine the temporal and spatial pattern of expression of key bone and cartilage proteins as atherosclerotic calcification progresses.


RESULTS
Using reverse transcription-polymerase chain reaction on a panel of noncalcified and calcified human arterial samples, two classes of proteins could be identified: (1) Matrix Gla protein, osteonectin, osteoprotegerin, and aggrecan were constitutively expressed by vascular smooth muscle cells (VSMCs) in the normal vessel media but downregulated in calcified arteries whereas (2) alkaline phosphatase, bone sialoprotein, osteocalcin, and collagen II were expressed predominantly in the calcified vessel together with Cbfa1, Msx2, and Sox9, transcription factors that regulate expression of these genes. In the calcified plaque in situ hybridization identified subsets of VSMCs expressing osteoblast and chondrocyte-like gene expression profiles whereas osteoclast-like macrophages were present around sites of calcification.


CONCLUSIONS
These observations suggest a sequence of molecular events in vascular calcification beginning with the loss of expression by VSMCs, of constitutive inhibitory proteins, and ending with expression by VSMCs and macrophages of chondrocytic, osteoblastic, and osteoclastic-associated proteins that orchestrate the calcification process.
Tyson
Kerry L
KL
Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Reynolds
Joanne L
JL
McNair
Rosamund
R
Zhang
Qiuping
Q
Weissberg
Peter L
PL
Shanahan
Catherine M
CM
D002114:Calcinosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D019902:Chondrocytes / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins; D015870:Gene Expression; D006609:High Mobility Group Proteins / Q000378:metabolism; D018398:Homeodomain Proteins; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009363:Neoplasm Proteins; D010011:Osteocytes / Q000378:metabolism*; D015676:Osteonectin / Q000378:metabolism; D055758:SOX9 Transcription Factor; D014157:Transcription Factors / Q000032:analysis* / Q000378:metabolism; D015854:Up-Regulation; D000097568:Matrix Gla Protein
D002135:Calcium-Binding Proteins; D050659:Core Binding Factor Alpha 1 Subunit; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D015676:Osteonectin; D055758:SOX9 Transcription Factor; D014157:Transcription Factors; D000097568:Matrix Gla Protein; C084119:MSX2 protein; C527932:SOX9 protein, human