Novel insight into PTH-Receptor Signaling through Mutations Causing Eiken Syndrome

• Applicant: Dr. Jakob Höppner
• Subject Area: Endocrinology, Diabetology, Metabolism ; Pediatric and Adolescent Medicine ; Nephrology ; Rheumatology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 535701562

Parathyroid hormone (PTH) is the key regulator of calcium and phosphate homeostasis as well as bone formation. The PTH-related peptide (PTHrP) is particularly important for slowing the differentiation of growth plate chondrocytes thus allowing normal bone growth. PTH and PTHrP, both mediate their actions through a shared G protein-coupled receptor (GPCR), the PTH/PTHrP receptor (PTH1R). Abnormal PTH1R function leads to several rare human diseases, which continue to provide novel insights into biological roles of PTH and PTHrP in common diseases. For example, homozygous "loss-of-function" PTH1R mutations cause Blomstrand's neonatal lethal chondrodysplasia, which is characterized by premature growth plate closure thereby preventing normal bone growth. In contrast, heterozygous "gain-of-function" PTH1R variants result in Jansen's metaphyseal chondrodysplasia, a disease characterized by delayed chondrocyte maturation that results in failure to form hypertrophic chondrocytes and trabecular bone. As Blomstrand’s disease, Eiken syndrome is caused by homozygous PTH1R mutations. However, Eiken syndrome is characterized by under-mineralized bones, thus suggesting a gain-of-function effect of PTH1R as seen in Jansen’s disease. Nevertheless, some patients with Eiken syndrome patients also exhibit additional clinical phenotype changes that are more consistent with loss-of-function in PTH1R. Defining the divergent and pleiotropic effects of mutant PTH1Rs that cause rare human diseases will provide new insights into the complex interrelationships by which PTH1R signaling in cartilage, bone, and kidney contributes to normal skeletal growth and mineral ion homeostasis and thus is likely to provide novel therapeutic approaches for a multitude patients affected by common disorders. Therefore, the aim of this project is to provide a comprehensive and in-depth characterization of the bone and kidney phenotype in mice expressing mutant parathyroid hormone receptors that cause Eiken syndrome, as well as detailed in vitro and in vivo studies to explain the sometimes contradictory phenotypes caused by these mutations in PTH1R. In addition, we will test the hypothesis that pharmacological manipulation of PTH1R function can normalize both skeletal and renal manifestations. The ongoing development of inverse PTH agonists at the PTH1R is likely to improve or prevent the chondrocyte mature defect. In addition, such PTH analogs will function also as competitive antagonists, which may have therapeutic potential for the treatment of PTH- or PTHrP-dependent hypercalcemia. Furthermore, these studies will provide important insights into the fundamentals of signaling pathways and regulation of G protein-coupled receptors in general and are thus of great importance beyond rare diseases.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Harald Jüppner