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Abstract: SA-OR105

Inhibition of Tissue-Nonspecific Alkaline Phosphatase Protects against Medial Arterial Calcification in the CKD-MBD Mouse Model

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Tani, Takashi, Nippon Medical School, Tokyo, Japan
  • Fujiwara, Meguji, Nippon Medical School, Tokyo, Japan
  • Orimo, Hideo, Nippon Medical School, Tokyo, Japan
  • Shimizu, Akira, Nippon Medical School, Tokyo, Japan
  • Tsuruoka, Shuichi, Nippon Medical School, Tokyo, Japan
  • Pinkerton, Anthony B., Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States
  • Millan, Jose luis, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, United States
Background

Medial arterial calcification (MAC), the main manifestation of chronic kidney disease - mineral and bone disorder (CKD-MBD), is a serious complication of patients with CKD. The overexpression of tissue-nonspecific alkaline phosphatase (TNAP) on vascular smooth muscle cells is reported to accelerate MAC formation. The aim of this study was to assess the inhibitory effect of SBI-425, novel and potent pharmacological TNAP inhibitor, on MAC formation in a CKD-MBD mouse model.

Methods

Eight-week-old C57/BL6J male mice in CKD groups (Vehicle, SBI-10 and SBI-30) (n=10 each) mice were fed a 0.2% adenine and 0.8% phosphorus (Pi) diet for 6 weeks to induce CKD, followed by a high phosphorus (0.2% adenine and 1.8% Pi) diet for 6 weeks. Mice in the SBI-10 and SBI-30 groups were administrated 10mg/kg and 30mg/kg of SBI-425 by gavage once per day, respectively, from 14 to 20 weeks of age. Control group mice (n=6) were fed a standard chow (0.8% Pi) from 8 to 20 weeks of age. At sacrifice, animals were scanned by computed tomography (CT) and aorta, kidney and blood samples were harvested.

Results

In contrast to major MAC formation in the vehicle group, administration of SBI-425 drastically halted MAC formation confirmed by aortic calcification volume (CT imaging), percentage calcified area in histology (positive Von Kossa staining) and aortic tissue calcium content (OCPC assay). Aortic tissue mRNA expression of osteoblastic trans-differentiation-related genes including TNAP were upregulated in the Vehicle group, while they were suppressed to Control levels in the SBI-10 and SBI-30 groups. Plasma and aortic tissue TNAP activities were increased in the Vehicle group, and they were suppressed by SBI-425 administration. Blood levels of urea nitrogen and creatinine, phosphorus, intact PTH and FGF-23 were higher in the CKD groups than in the Control group and were comparable between CKD groups. Plasma pyrophosphate (PPi) levels were shown to be higher in SBI-10 and SBI-30 group than the others.

Conclusion

These results showed that TNAP inhibition protects the vascular media from MAC formation in a mouse model of CKD-MBD. As PPi is a potent protective agent for calcification, elevated PPi concentrations in the SBI-425 treated groups, resulting from TNAP activity suppression, reduced MAC.