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Abstract: TH-OR12

The Calcified Vasculature in CKD Secretes Signal Proteins That Inhibit Bone Mineralization

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Mace, Maria Lerche, Rigshospitalet, Copenhagen, Denmark
  • Gravesen, Eva, Dept of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
  • Egstrand, Søren, Rigshospitalet, Copenhagen, Denmark
  • Nordholm, Anders, Rigshospitalet, Copenhagen, Denmark
  • Morevati, Marya, Rigshospitalet, Copenhagen, Denmark
  • Olgaard, Klaus, Rigshospitalet, Copenhagen, Denmark
  • Lewin, Ewa, Rigshospitalet, Copenhagen, Denmark
Background

Our group has recently demonstrated that CKD-induced vascular calcification impairs bone formation & mineralization in an in vivo model by transplanting calcified aortas from CKD rats into healthy recipients. Aim was to confirm our hypothesis of a direct crosstalk between the vasculature & bone in in vitro experiments.

Methods

Vascular calcification was induced in uremic Wistar rats. Normal aortas (NA) & uremic calcified aortas (CA) were incubated ex vivo or co-incubated with UMR-106 cell line (UMR). Media was measured for Wnt inhibitors sclerostin (Scl), Dkk1, SFRP4 & activin A (Act A). UMR-106 cell mineralization stained with Alizarin red. Signal pathways were analyzed by PCR and WB.

Results

CA completely inhibited mineralization in UMR-106 cells (Figure 1). Mineralization inhibitor osteopontin (OPN) mRNA & protein were highly upregulated in UMR+CA (OPN mRNA UMR+CA 25.50 [5.53-51.00], UMR+NA 2.78 [1.20-7.85], UMR 0.80 [0.39-5.49], p<0.001). Induction of OPN was abolished by LiCl. ANKH was upregulated in UMR+UA (2.95 [1.87-7.32], UMR+NA 1.75 [0.51-2.46], UMR 0.96 [0.49-2.15], p<0.01), whereas same levels of Alpl were found. Similar expressions of β-catenin protein & Wnt target genes c-Myc & Ccnd1 were found. However, Jun was upregulated in UMR+NA & UMR+CA (UMR 0.94 [0.61-2.83] vs. UMR+NA 1.58 [1.18-2.29] vs. UMR+CA 1.98 [1.08-3.44], p< 0.01). The CA secreted large amounts of Scl (1936 [495-4400] vs. NA 31 [7-88] pg/ml, p=0.002), Dkk1 (353 [110-686] pg/ml vs. none in NA), and Act A (12158 [4712-18000] vs. NA 1838 [250-4146] pg/ml, p=0.002). NA & CA secreted SFRP4.

Conclusion

The present study confirms our hypothesis on a direct crosstalk between vasculature and bone. The uremic calcified aorta secretes signal molecules that inhibit bone mineralization .

Funding

  • Private Foundation Support