The Braddock Lab in the Department of Pathology at Yale School of Medicine has found that mammalian bone mass is regulated by catalysis independent ENPP1 protein signaling pathways. The study was published on June 30, 2022, in the Journal of Bone and Mineral Research; Demetrios Braddock, MD, PhD, associate professor of pathology at Yale School of Medicine, is senior author, with collaborators including Thomas Carpenter in Pediatric Endocrinology at Yale and Ralf Oheim in Osteology and Biomechanics at the University of Hamburg Medical Center. The finding reveals the molecular pathway for early onset osteoporosis observed in patients with heterozygous ENPP1 deficiency that the same team reported in March of 2020 (‘Human heterozygous ENPP1 deficiency induces early onset osteoporosis, a phenotype recapitulated in murine homozygous Enpp1 deficiency’. J Bone Miner Res. 2020 Mar;35(3):528-539).
ENPP1 deficiency induces vascular/soft tissue calcifications in Generalized Arterial Calcification of Infancy (GACI), and low bone mass with phosphate-wasting rickets in GACI survivors. ENPP1 haploinsufficiency induces early-onset osteoporosis and mild phosphate-wasting in adults. Both conditions demonstrate the unusual combination of reduced accrual of skeletal mineral, yet excess and progressive heterotopic mineralization, the study notes.
ENPP1 is the only enzyme that generates extracellular pyrophosphate (PPi), a potent inhibitor of bone and heterotopic mineralization. Researchers developed a murine model uncoupling ENPP1 protein signaling from ENPP1 catalysis to determine the impact of an ENPP1 deficiency.
“This novel mouse model demonstrated that mammalian bone mass is regulated by catalysis independent ENPP1 protein signaling pathways, which provides a rational understanding for the early onset osteoporosis observed in patients with heterozygous ENPP1 deficiency,” Braddock said.