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Abstract: FR-PO483

TNAP Inhibition: A Novel Strategy to Prevent the Development of Vascular Calcification?

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Opdebeeck, Britt, University Antwerp, Wilrijk, Belgium
  • Verhulst, Anja, University of Antwerp, Wilryk, antwerp, Belgium
  • D'Haese, Patrick C., University Antwerp, Wilrijk, Belgium
  • Neven, Ellen, University of Antwerp, Wilryk, antwerp, Belgium
Background

Vascular media calcification (VC) is frequently seen in chronic kidney disease patients. Pyrophosphate (PPi) is a well-known calcification inhibitor that binds to nascent hydroxyapatite crystals and prevents further incorporation of inorganic phosphate (Pi) into these crystals. However, the enzyme tissue non-specific alkaline phosphatase (TNAP), which is highly expressed in calcified arteries, degrades extracellular PPi into Pi ions, by which PPi loses its ability to block VC. Here, we aimed to evaluate whether a TNAP-inhibitor is able to prevent the development of arterial calcification in a rat model of warfarin-induced VC.

Methods

To induce VC, rats received a diet containing 0.30% warfarin and 0.15% vitK1 throughout the entire study and were subjected to the following daily treatments: (i) vehicle (n=10) or (ii) 10 mg/kg/day TNAP-inhibitor (n=10) administered via an i.p. catheter from start of the study until sacrifice at wk7. Calcium (Ca) and phosphorus (P) levels were determined in serum and urine samples being important determinants of VC.To evaluate osteo/chondrogenic switch of vascular smooth muscle cells (VSMCs), aortic mRNA expression of runx2, TNAP, SOX9, collagen1 and 2 was analyzed by qPCR. At sacrifice, VC was evaluated by measurement of the total Ca content in the arteries and quantification of the area % calcification on Von Kossa stained aortic sections.

Results

No difference in serum Ca and P levels was observed between both study groups. Warfarin exposure resulted in distinct calcification in the aorta and peripheral arteries in vehicle treated rats. Importantly, daily treatment with a TNAP-inhibitor significantly reduced VC as indicated by a significant decrease in calcium content in the aorta (mean ± SEM; vehicle 3.84±0.64 mg Ca/g wet tissue vs TNAP-inhibitor 0.70±0.23 mg Ca/g wet tissue) and peripheral arteries and a distinct reduction in area % calcification on Von Kossa stained aortic sections as compared to vehicle condition. TNAP-inhibitor treatment did not alter the mRNA expression of osteo/chondrogenic marker genes runx2, TNAP, SOX9, collagen1 and 2.

Conclusion

Treatment with a TNAP-inhibitor significantly reduced the development of VC in the aorta and peripheral vessels of warfarin exposed rats most probably by directly interfering with the apatite formation rather than promoting osteo/chondrogenic conversion of VSMCs.

Funding

  • Government Support - Non-U.S.