Enpp1 enzyme replacement restores bone mass in murine model of Enpp1 associated osteoporosis

摘要

Human heterozygous ecto-nucleotide pyrophosphatase/ phosphodiesterase (ENPP1) deficiency results in mild elevation of FGF23, mild phosphate wasting, intermediate levels of plasma pyrophosphate, and early onset osteoporosis (EOOP), a phenotype recapitulated in homozygous Enpp1 deficient mice (Enpp1 asj/asj ). To determine whether Enpp1 enzyme replacement would affect bone mass, we compared the skeletal phenotype of WT and Enpp1 asj/asj mice treated with Enpp1-Fc or vehicle on a low magnesium, high phosphate diet to exacerbate the mineralization deficiency ('acceleration diet'). We found that, like Enpp1 asj/asj mice fed normal chow for 10 weeks, Enpp1 asj/asj mice fed the acceleration diet for 5 weeks exhibit decreased trabecular bone mass (Tb. BV/TV 70%, Tb.Sp 125%, and TbN 82% of WT) and reduced cortical bone mass (Ct. BV/TV 90% and Ct. Thickness 72% of WT). Also similar to 10-week Enpp1 asj/asj mice fed normal chow, tibias of 5-week Enpp1 asj/asj mice fed acceleration diet exhibited less favorable biomechanics (maximum load, stiffness, and total work of 52%, 45%, and 27% of WT, respectively). Treating the Enpp1 asj/asj mice between weeks 2-5 with Enpp1-Fc normalized trabecular bone mass parameters, and normalized or improved bone biomechanical properties (normalized maximum load compared to WT, improved stiffness to 74% and total work to 63% of WT) and cortical bone mass (improved Ct. BV/TV to 92% and Ct.Th to 81% of WT). Furthermore, qBEI showed no significant differences in BMDD or osteocyte lacunae of mice on 'acceleration diet' (treated or untreated). Finally, a consequence of the acceleration diet was renal failure due to tissue mineralization in untreated Enpp1 asj/asj mice, which appeared after week 4 and was prevented with ENPP1-Fc. However, no histological findings specific for renal osteodystrophy, including histomorphometry and qBEI, were detected, suggesting that renal osteodystrophy did not develop in the untreated mice. Our results suggest that bone mass in Enpp1 deficiency may respond to Enpp1 enzyme replacement therapy.