High circulating fibroblast growth factor 23 (FGF23) levels are probably a major risk factor for cardiovascular disease in chronic kidney disease. FGF23 interacts with the receptor FGFR4 in cardiomyocytes inducing left ventricular hypertrophy. Moreover, in the liver FGF23 via FGFR4 increases the risk of inflammation which is also found in chronic kidney disease. In contrast, X-linked hypophosphatemia is characterized by high FGF23 circulating levels due to loss of function mutations of the phosphate-regulating gene with homologies to an endopeptidase on the X chromosome (PHEX), but is not characterized by high cardiovascular morbidity. Here we used a novel murine X-linked hypophosphatemia model, the Phex mouse line, bearing an amino acid substitution (p.Cys733Arg) to test whether high circulating FGF23 in the absence of renal injury would trigger cardiovascular disease. As X-linked hypophosphatemia patient mimics, these mice show high FGF23 levels, hypophosphatemia, normocalcemia, and low/normal vitamin D levels. Moreover, these mice show hyperparathyroidism and low circulating soluble αKlotho levels. At the age of 27 weeks we found no left ventricular hypertrophy and no alteration of cardiac function as assessed by echocardiography. These mice also showed no activation of the calcineurin/NFAT pathway in heart and liver and no tissue and systemic signs of inflammation. Importantly, blood pressure, glomerular filtration rate and urea clearance were similar between genotypes. Thus, the presence of high circulating FGF23 levels alone in the absence of renal impairment and normal/high phosphate levels is not sufficient to cause cardiovascular disease.

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Roux-en-Y gastric bypass (RYGB) surgery leads to bone loss in humans, which may be caused by vitamin D and calcium malabsorption and subsequent secondary hyperparathyroidism. However, because these conditions occur frequently in obese people, it is unclear whether they are the primary causes of bone loss after RYGB. To determine the contribution of calcium and vitamin D malabsorption to bone loss in a rat RYGB model, adult male Wistar rats were randomized for RYGB surgery, sham-operation-ad libitum fed, or sham-operation-body weight-matched. Bone mineral density, calcium and phosphorus balance, acid-base status, and markers of bone turnover were assessed at different time points for 14 wk after surgery. Bone mineral density decreased for several weeks after RYGB. Intestinal calcium absorption was reduced early after surgery, but plasma calcium and parathyroid hormone levels were normal. 25-hydroxyvitamin D levels decreased, while levels of active 1,25-dihydroxyvitamin D increased after surgery. RYGB rats displayed metabolic acidosis due to increased plasma lactate levels and increased urinary calcium loss throughout the study. These results suggest that initial calcium malabsorption may play a key role in bone loss early after RYGB in rats, but other factors, including chronic metabolic acidosis, contribute to insufficient bone restoration after normalization of intestinal calcium absorption. Secondary hyperparathyroidism is not involved in postoperative bone loss. Upregulated vitamin D activation may compensate for any vitamin D malabsorption.