Understanding the cellular and molecular causes of early-onset osteoporosis associated with Enpp1 haploinsufficiency

• Applicant: Professor Dr. Ralf Oheim
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497276025

ENPP1 is a cell-surface enzyme generating inorganic pyrophosphate (PPi), which serves as a potent inhibitor of matrix mineralization. Biallelic loss-of-function mutations in ENPP1 result in Generalized Arterial Calcification of Infancy (GACI), a rare neonatal disorder characterized by arterial calcifications causing death in approximately 50% of the affected individuals around 6 months of age. Homozygous inactivating mutations in ENPP1 were also found to cause Autosomal Recessive Hypophosphatemic Rickets (ARHR), a disease characterized by rachitic skeletal deformities due to low serum phosphate levels, which is triggered by excess production of the phosphaturic hormone FGF23. The complexities of ENPP1 functions in physiological and pathologic mineralization were further enhanced by our recent identification of heterozgous ENPP1 mutations in individuals with early-onset osteoporosis (EOOP).This project aims at establishing a mouse model of ENPP1-dependent EOOP in order to provide a better understanding regarding the impact of ENPP1 haploinsufficiency on the skeleton and to define the optimal treatment for the respective patients. More specifically, we will apply a deep phenotyping approach to analyze aged Enpp1+/asj-2J mice, carrying a heterozygous Enpp1 deletion, by the means of µCT, undecalcified histology, bone-specific histomorphometry, quantitative backscattered electron imaging, as well as serum and transcriptome analyses. We will also treat these mice by anti-resorptive and osteoanabolic drugs and evaluate whether activation of the Wnt signaling pathway improves their skeletal phenotype. Finally, we will take advantage of homozygous Enpp1asj-2J/asj-2J mice for phenotypic analysis and cell culture experiments with primary osteoblasts to provide a better molecular understanding regarding the role of ENPP1 in biomineralization and phosphate homeostasis.Since the work programme mostly relies on methods that are well established at our Institute, we do not envision major experimental problems arising during the course of the project. We are convinced that the respective data will not only be relevant from a basic science perspective, but that they will also help to optimize the treatment of patients carrying ENPP1 mutations.

• DFG Programme: Research Grants