Harald Jueppner, MD, is the Chief of Pediatric Nephrology at the Massachusetts General Hospital and a Professor of Pediatrics at Harvard Medical School.
He has had a long-standing interest in the regulation of calcium and phosphate homeostasis as well as the mechanisms contributing to bone growth and turnover. He and his colleagues were the first to isolate cDNAs encoding the PTH/PTHrP receptor (PTHR1), which allowed the search for human disorders caused by mutations in this gene. Initially it was thought that such mutations are the cause of pseudohypoparathyroidism types Ib (PHP1B); however, his group excluded such mutations, subsequently mapped the genetic locus for the autosomal dominant form of PHP1B (AD-PHP1B) to the GNAS complex locus on chromosome 20q13, and eventually showed that deletions in GNAS or STX16 are disease-causing.
Instead, Dr. Jueppner’s group identified several different, activating mutations in Jansen’s metaphyseal chondrodysplasia (JMC), which is characterized by severe and crippling bone deformities, short-limbed dwarfism, and hypercalcemia. Expression of the PTHR1 mutant under the control of the type II collagen promoter (Col2-H223R-PTHR1) in mice resulted in a significant delay in chondrocyte differentiation, while expression of one of the mutant receptors under the control of the collagen type I promoter (Col1-H223R-PTHR1) resulted in massive new bone formation.
Together with Dr. Gardella, Dr. Jueppner now explores in vitro and in vivo the role of inverse agonists at the PTHR1 for the treatment of growth plate and bone abnormalities observed in the currently available transgenic mouse JMC models.