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Abstract: FR-PO304

Reversibility of Vascular Calcifications

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • O'Neill, W. Charles, Emory University School of Medicine, Atlanta, Georgia, United States
  • Wang, Xiaonan H., Emory University School of Medicine, Atlanta, Georgia, United States
  • Weitzmann, Mervyn Neale, Emory University School of Medicine, Atlanta, Georgia, United States
Background

Mechanisms of vascular calcification have been extensively studied but little is known about resorption of existing calcifications, which has important therapeutic implications. Current data suggest that vascular calcification is largely irreversible but potential mechanisms for resorption that could be exploited have not been explored. To this end, resorption of calcifications was examined in human arteries implanted subcutaneously in mice or cultured with macrophages, and compared to bone particles and hydroxyapatite (HA).

Methods

Calcified human arteries were obtained from amputation specimens and calcification was quantified by µCT before and after implantation. Devitalized bone particles were obtained by pulverizing mouse femurs in liquid N2 after removal of marrow, and HA was obtained commercially. Calcium content was measured after acid extraction. Standard histology protocols were used and activity of tartrate-resistant acid phosphatase (TRAP), a marker of osteoclasts, was measured in Triton extracts. Arteries or bone particles were cultured with macrophages from mouse spleens in the presence of M-CSF and TNFα +/- receptor activator of nuclear factor κ-Β ligand (RANKL) to induce osteoclast formation.

Results

There was no decrease in arterial calcifications up to 6 weeks after implantation (+2.8 ± 0.6%) and only slight, insignificant resorption of bone particles after 7 weeks (-10 ± 8%). By contrast, only 24 ± 7% of hydroxyapatite remained after 7 weeks. Osteoclasts were not observed in any implant although TRAP-negative multinucleated giant cells were observed in HA implants. Calcified arteries cultured with macrophages for 9 days showed a 34 ± 4% increase in medium calcium (p=0.01) consistent with resorption, without enhancement by RANKL. Findings were similar with bone particles.

Conclusion

Hydroxyapatite is resorbed in vivo by macrophages in an osteoclast-independent manner. This does not occur with vascular calcifications in vivo but can occur in vitro with added macrophages, suggesting that vascular calcification is not reversible in vivo due to the failure to form functional osteoclasts or recruit macrophages. Similar findings in bone particles suggest that this extends to other forms of biomineralization. Further studies are needed to determine the properties of vascular calcifications that prevent recruitment of resorptive cells and identify strategies to overcome this.

Funding

  • Private Foundation Support