Jansen’s metaphyseal chondrodysplasia (JMC) is a rare autosomal disorder characterized by malfunction of the temporomandibular joint (TMJ) among other bone deformities that are associated with hypercalcemia and hypophosphatemia. Caused by constitutive activation of genetically dominant heterozygous mutants of the parathyroid hormone (PTH) type 1 (PTHR) receptor, the cell surface receptor for PTH and its related protein (PTHrP), there is no cure or efficient therapeutic drug for JMC patients.
The goal of a new research effort funded by the NIH’s National Institute of Dental & Craniofacial Research is to identify effective small (non-peptidic) molecules for directly blocking anomalous constitutive activity of PTHR JMC mutants while maintaining the action of endogenous ligands (PTH and PTHrP). The project entitled, “Identification of selective inhibitors of PTH-receptor for Jansen’s metaphyseal chondrodysplasia,” began on September 1, 2022, for 2 years. The project’s co-principal investigator is McGowan Institute for Regenerative Medicine affiliated faculty member Juan Taboas, PhD (pictured), Associate Professor with the Department of Oral and Craniofacial Sciences in the School of Dental Medicine and the Department of Biomedical Engineering in the Swanson School of Engineering at the University of Pittsburgh.
The abstract for this project reads:
The objective of this project is to test and optimize our recently identified small non-peptidic molecules (referred to as Pitt molecules) to restore normal parathyroid hormone type 1 receptor (PTHR) signaling and cellular temporomandibular joint (TMJ) condylar morphogenic processes, which are defective in cells expressing constitutive active receptor mutants causing Jansen’s metaphyseal chondrodysplasia (JMC). Based on existing collaborations between PIs (Dr. Vilardaga, Dept. of Pharmacology & Chem. Biol., and Dr. Taboas, Dept. Oral and Craniofacial Sciences, and of Bioengineering) and co-I (Wipf, Dept. of Chemistry) at U.Pitt, an interdisci- plinary approach has been developed to demonstrate the efficacy of Pitt molecules in restoring normal PTHR signaling and cellular morphogenic processes in vitro, and thereby better understand the effects of PTHR signaling on condylar morphogenesis. The project has 2 aims: Aim 1 will identify the most effective allosteric small molecules for blocking constitutive PTHR activation using state-of-the-art optical analysis of receptor signaling in live cells expressing PTHR mutants encountered in JMC patients (PTHR-H223R, PTHR-T410P, or PTHR-I458R), and medicinal chemistry methods to optimize blocking properties of Pitt molecules. Aim 2 will take a step further by determining the effect of small molecules on temporomandibular joint condylar morphogenesis using biochemical and histological assays on engineered microtissues composed of condylar mesenchymal progenitors from wild-type and mice expressing the JMC mutant PTHR-H223R. The significance of this research program lies in its premise to better understand the effects of PTHR signaling on condylar morphogenesis and lay the groundwork for a future translational research program that examines the therapeutic utility of these Pitt molecules for treatment of temporomandibular disorders.
Congratulations, Dr. Taboas!
NIH Reporter: Identification of selective inhibitors of PTH-receptor for Jansen’s metaphyseal chondrodysplasia