Does Fgf23-klotho activity influence vascular and soft tissue calcification through regulating mineral ion metabolism?

Abstract

Recent studies describe a novel role of fibroblast growth factor-23 (Fgf23)-klotho activity in the systemic regulation of calcium and phosphate homeostasis. Both Fgf23 and klotho ablated mice develop extensive vascular and soft tissue calcification. Inability to clear the required amount of phosphate by the kidney, due to the absence of Fgf23-klotho activity, leads to increased accumulation of serum phosphate in these genetically modified mice, causing extensive calcification. Serum calcium and 1,25 hydroxyvitamin D levels are also elevated in both Fgf23 and klotho ablated mice. Moreover, increased sodium phosphate co-transporter activity in both Fgf23 and klotho ablated mice increases renal phosphate reabsorption which in turn can facilitate calcification. Collectively, these observations bring new insights into our understanding of the roles of the Fgf23-klotho axis in the development of vascular and soft tissue calcification.

Figure 1

Immunostaining of NaPi2a protein in kidneys obtained from control (A), Fgf23^−/− (B) and klotho^−/− (C) mice. An increased expression of NaPi2a protein is detected in Fgf23^−/− and klotho^−/− mice, compared to wild-type mice. Please note that NaPi2a protein is exclusively present in the lumnal side of the proximal tubular epithelial cells.

Figure 2. Soft tissue and vascular calcification in Fgf-23^−/− mice

von Kossa staining on paraffin sections of the kidney (A, B) and lung (C, D), showing widespread renal (B) and pulmonary (D) calcifications in Fgf-23^−/− mice. No such calcification is noted in the wild-type littermates (A, C). Arrows depict the calcified vessels in the kidney and lung of the Fgf-23^−/− mice. (Magnification: kidney ×20; lung ×10).