The phosphate-lowering effect of nicotinamide is offset by reduced Fgf23 levels in a murine model of familial tumoral calcinosis

Abstract

Familial tumoral calcinosis is caused by mutations in the GALNT3 gene. Lack of GalNAc transferase 3, encoded by GALNT3, destabilizes FGF23, a key hormone that suppresses phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis in the kidney. The destabilized FGF23 is more susceptible to proteolytic cleavage, thereby reducing the secretion of biologically active intact FGF23. Persistent hyperphosphatemia due to decreased FGF23 concentrations leads to often large, ectopic calcific masses in soft tissues, which are usually removed surgically. However, the calcific masses often recur, requiring a more permanent solution to the problem. Nicotinamide is reported to lower serum phosphate by decreasing type IIb sodium-dependent phosphate cotransporter in the gut. This effect of nicotinamide has promoted its use in treatment of limited cases of tumoral calcinosis, though its effectiveness remains largely unclear. Therefore, we investigated nicotinamide as a potential therapy for tumoral calcinosis, using a murine model of the disease – Galnt3 knockout mice. Initially, nicotinamide (doses 0, 2.5, 5, 7.5, and 10 mmol/kg/day) was given to normal mice for 2 weeks. Treatment had no effect on serum phosphate levels; however, Fgf23 was decreased in a dose-dependent manner. Subsequently, high-dose nicotinamide (10 mmol/kg/day) was tested for 4 weeks in Galnt3 knockout mice on a high-phosphate diet. The radiographic data pretreatment and posttreatments showed that the treatment did not eliminate the calcification, but retarded its growth, while in the untreated mice, calcifications increased in size. The therapy did not change serum phosphate levels despite moderately increased phosphate excretion, likely due to decreased serum intact Fgf23 levels. Quantification of calcium and phosphate contents in hearts and kidneys revealed that the treated mice had significantly high calcium in the heart. In summary, nicotinamide did not alter serum phosphate levels because the phosphate-lowering effect of nicotinamide was diminished by reduction in intact Fgf23 concentrations. The increased calcium in the heart suggests that nicotinamide therapy may also have an adverse effect.