Ectopic calcification is a common response to soft tissue injury, and can lead to devastating clinical consequences when present in heart valves or blood vessels. It is hypothesized that vascular mesenchymal and inflammatory cells normally maintain the balance between pro- calcific and anti-calcific regulatory proteins in vascular tissues such that ectopic deposition of apatite is avoided. Alterations in this balance induced by injury or disease is postulated to induce ectopic apatite deposition. We have developed in vitro and in vivo models of ectopic vascular calcification and found that: 1) elevated extracellular phosphate levels induce smooth muscle cell (SMC) culture mineralization morphologically similar to that observed in calcified human valves and atherosclerotic plaques; 2) SMC culture mineralization is associated with a dramatic loss of SMC-specific gene expression and gain of osteoblast-like properties, including expression of CBFA-1; 3) osteopontin is abundant in macrophages associated with human and mouse calcified atherosclerotic and valvular lesions; and 4) osteopontin is a potent inhibitor of vascular cell calcification in vitro. This proposal will examine factors which mediate the pro-mineralizing phenotypic state of vascular mesenchymal cells, the role of intracellular phosphate signaling in controlling this phenotype, and the structure and function of osteopontin in inhibiting ectopic mineralization. In addition, mutant mice will be used to define the role of inflammatory cell types and major bone noncollagenous proteins in ectopic calcification of prosthetic valves. Finally, the role of osteopontin in regulating atherosclerotic calcification will be examined in ApoE X OPN double knockout mice. These studies will identify underlying mechanisms regulating ectopic mineralization, and identify novel strategies to prevent native and prosthetic vascular calcification.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL062329-01
Application #
2827377
Study Section
Pathology A Study Section (PTHA)
Project Start
1999-04-01
Project End
2003-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Washington
Department
Pathology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Yamada, Shunsuke; Leaf, Elizabeth M; Chia, Jia Jun et al. (2018) PiT-2, a type III sodium-dependent phosphate transporter, protects against vascular calcification in mice with chronic kidney disease fed a high-phosphate diet. Kidney Int 94:716-727
Yamada, Shunsuke; Wallingford, Mary C; Borgeia, Suhaib et al. (2018) Loss of PiT-2 results in abnormal bone development and decreased bone mineral density and length in mice. Biochem Biophys Res Commun 495:553-559
Scatena, Marta; Jackson, Melissa F; Speer, Mei Y et al. (2018) Increased Calcific Aortic Valve Disease in response to a diabetogenic, procalcific diet in the LDLr-/-ApoB100/100 mouse model. Cardiovasc Pathol 34:28-37
Wallingford, Mary Catherine; Chia, Jia Jun; Leaf, Elizabeth M et al. (2017) SLC20A2 Deficiency in Mice Leads to Elevated Phosphate Levels in Cerbrospinal Fluid and Glymphatic Pathway-Associated Arteriolar Calcification, and Recapitulates Human Idiopathic Basal Ganglia Calcification. Brain Pathol 27:64-76
Yamada, Shunsuke; Giachelli, Cecilia M (2017) Vascular calcification in CKD-MBD: Roles for phosphate, FGF23, and Klotho. Bone 100:87-93
Giachelli, Cecilia M; Speer, Mei Y (2017) Noncanonical Wnts at the Cusp of Fibrocalcific Signaling Processes in Human Calcific Aortic Valve Disease. Arterioscler Thromb Vasc Biol 37:387-388
Paloian, Neil J; Leaf, Elizabeth M; Giachelli, Cecilia M (2016) Osteopontin protects against high phosphate-induced nephrocalcinosis and vascular calcification. Kidney Int 89:1027-1036
Wallingford, Mary C; Gammill, Hilary S; Giachelli, Cecilia M (2016) Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and laminin?1 expressing cells. Reprod Biol 16:13-26
Lin, Mu-En; Chen, Theodore; Leaf, Elizabeth M et al. (2015) Runx2 Expression in Smooth Muscle Cells Is Required for Arterial Medial Calcification in Mice. Am J Pathol 185:1958-69
Chavkin, Nicholas W; Chia, Jia Jun; Crouthamel, Matthew H et al. (2015) Phosphate uptake-independent signaling functions of the type III sodium-dependent phosphate transporter, PiT-1, in vascular smooth muscle cells. Exp Cell Res 333:39-48

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