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Abstract: SA-OR102

Dietary Magnesium Prevents Vascular Calcification and Bone Mineralization in Klotho Knock-Out Mice

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Ter Braake, Anique D., Radboud University Medical Center, Nijmegen, Netherlands
  • Alkema, Wynand, Radboud University Medical Center, Nijmegen, Netherlands
  • Hoenderop, Joost, Radboud University Medical Center, Nijmegen, Netherlands
  • De Baaij, Jeroen H.F., Radboud University Medical Center, Nijmegen, Netherlands
Background

Klotho is a key modulator of the phosphate (Pi) and calcium (Ca2+) balance and is diminished in chronic kidney disease (CKD). Klotho knock-out (-/-) mice are therefore an important model for CKD, mimicking all essential features including hyperphosphatemia and development of calcification. In CKD, serum magnesium (Mg2+) inversely correlates with incidence and severity of vascular calcification. The mechanisms by which Mg2+prevents vascular calcification are poorly understood. Therefore, this study aims to determine the effects of Mg2+on development of aortic calcification using Klotho-/-mice.

Methods

Klotho-/-and Klotho+/+mice were fed a normal (0.05% w/w) or high (0.48% w/w) Mg2+diet from birth. Aortic calcification was detected by Von Kossa staining and RNA-sequencing was performed. Serum electrolyte and hormone concentrations were determined. MicroCT was used to study bone integrity.

Results

Von Kossa staining revealed that aortic calcification developed extensively in Klotho-/-mice on a normal Mg2+diet and was absent in Klotho+/+mice. Strikingly, high Mg2+diet prevented calcification in Klotho-/-mice. Moreover, Mg2+rescued increased expression of RUNX2 and osteopontin as well as upregulation of matrix gla protein, demonstrating the preventive effect of Mg2+on pro-osteogenic signaling. Potential novel mechanisms by which Mg2+prevented calcification were studied by RNA sequencing, revealing that pathways mediating inflammation and extracellular matrix remodeling enriched in Klotho-/-mice were reversed by Mg2+. Though Mg2+prevented calcification, klotho-/-mice on high Mg2+diet had reduced weight and smaller stature. Interestingly, high Mg2+impaired bone formation in Klotho-/-mice as femoral mineral-bone density decreased by 20% compared to mice on normal Mg2+ diet. High Mg2+did not change known mineralization modulators parathyroid hormone, 1.25-dihydroxyvitamin D and Ca2+in serum. Interestingly, Mg2+prevented calcification despite increasing fibroblast growth factor-23 and Pi concentration in Klotho-/-mice.

Conclusion

This study shows that Mg2+prevented vascular calcification in Klotho-/-mice. Importantly, Mg2+prevented mineralization in the aortic media as well as bone, potentially involving anti-inflammatory signaling and disruption of extracellular matrix remodeling.

Funding

  • Government Support - Non-U.S.