Bone mineral loss damages renal tubules in mice

Fibroblast growth factor-23 (FGF23) is secreted from bone in response to increased phosphate influx into the blood following dietary phosphate loading. FGF23 acts on the kidney to increase urinary phosphate excretion by suppressing phosphate resorption at the proximal tubules. Although essential for maintaining phosphate balance, the increase in FGF23 increases the phosphate concentration in the renal tubular fluid. Once the phosphate concentration exceeds the solubility, calcium-phosphate microcrystals appear in the tubular fluid, leading to renal tubular damage and nephron loss. We hypothesized that an increase in bone resorption might mobilize phosphate stored in the bone into the blood and trigger the pathophysiology similar to dietary phosphate loading. Here we show that increased bone resorption increases blood FGF23 levels and damages renal tubules in mice. We stimulated bone resorption in mice by administrating soluble receptor activator of NF-κB ligand (sRANKL) or by placing them in a microgravity environment on the International Space Station and observed an increase in FGF23 and renal tubular damage. We also confirmed that pre-treatment with bisphosphonate, an inducer of osteoclast apoptosis, prevented the sRANKL-induced increase in FGF23 and renal tubular damage. These findings have raised the possibility that bone mineral loss may contribute to renal tubular damage in clinical settings, including acute kidney injury in hospitalized patients on bed rest, disuse osteoporosis, and chronic kidney disease-mineral bone disorder.