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Abstract: SA-OR106

The Direct Inhibitory Effect of Ferric Citrate on Phosphate-Induced Calcification and Osteoblastic Trans-Differentiation via Suppression of HIF1a Expression in Human Vascular Smooth Muscle Cells

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Tokumoto, Masanori, Fukuoka Dental College, Fukuoka, Japan
  • Yamada, Shunsuke, Kyushu University, Fukuoka, Japan
  • Nakano, Toshiaki, Kyushu University, Fukuoka, Japan
  • Tsuruya, Kazuhiko, Nara Medical School, Kashihara, Japan
  • Kitazono, Takanari, Kyushu University, Fukuoka, Japan
  • Ooboshi, Hiroaki, Fukuoka Dental College, Fukuoka, Japan

Vascular calcification is a life-threatening pathophysiological abnormality in chronic kidney disease (CKD). Phosphate (P) is known as its main inducer, and it was recently reported that P enhances HIF1a expression, leading to osteoblastic trans-differentiation and calcification of cultured vascular smooth muscle cells (VSMCs). Because iron degrades HIF1a via activation of proryl hydroxylase (PHD), we examined direct effects of ferric citrate (FC), an iron-containing P binder, on P-induced calcification, osteoblastic trans-differentiation, and HIF1a expression in VSMCs.


Human VSMCs were cultured in DMEM plus 10%FCS and 2.0mM P with 0, 1, 5, 10, 50, 100, or 500mM FC for one or two weeks. The precipitated calcium (Ca) contents and expression of calcification inducers or inhibitors were evaluated.


At 1 week, moderate to high concentrations (>=5mM) of FC equally decreased P-induced calcification by about 80% (p<0.01), while, at 2 weeks, FC inhibited calcification in a concentration-dependent manner and high concentrations (>=50mM) of FC reduced calcification by almost 90% (p<0.01). Moderate to high concentrations (>=5mM) of FC not only suppressed expression of osteoblastic trans-differentiation inducers (BMP2, RUNX2, SOX9, MSX2, PiT1, and MMP2), but also increased expression of calcification inhibitors, OPG and MGP (p<0.01). Moreover, moderate to high concentrations of FC inhibited expression of HIF1a and VEGF, a downstream gene of HIF1 (p<0.01). Expression of HIF1a and VEGF positively correlated with precipitated Ca content and expression of BMP2, RUNX2, SOX9, MSX2, PiT1, and MMP2, respectively (p<0.01), and negatively correlated with OPG and MGP expression (p<0.01).


FC, an iron-containing P binder, can directly inhibit P-induced calcification and osteoblastic trans-differentiation via suppression of HIF1a expression in cultured human VSMCs.


  • Government Support - Non-U.S.