Jansen's Metaphyseal Chondrodysplasia (JMC) is a rare developmental disease caused by activating, gain- of-function mutations in the PTH1R, the receptor for parathyroid hormone (PTH) and PTH-related peptide (PTHrP). The PTH1R mutations lead to abnormal skeletal development resulting in severe, crippling bone deformities, and extremely short stature. In addition, JMC patients develop chronic, often severe hypercalcemia and hypercalciuria that contribute to development of chronic kidney disease (CKD) later in life, necessitating kidney replacement therapy in older adults. There is currently no cure or effective treatment for JMC, despite a clearly defined molecular target. We previously developed several PTH-PTHrP analogs that show inverse agonism when tested in cells expressing different constitutively active PTH1Rs, including the H223R-PTH1R mutant. Our extensive preliminary studies have shown that one inverse agonist, namely L11,dW12,W23,Y36-PTHrP(7-36) (dTrp12-PTHrP(7-36)), reverses in vivo effects induced by the H223R-PTH1R mutant expressed via the type I collagen promoter (Col1-H223R mice), thus reducing bone turnover and cortical bone loss, and improving bone length. We now plan to provide further documentation that this PTH analog, or a derivative thereof, can prevent the growth plate abnormalities, which occur in mice expressing the H223R-PTH1R mutant in proliferating chondrocytes via the type II collagen promoter (Col2-H223R mice); homozygous Col2-H223R mice are small, just like JMC patients, and it is plausible that pre- and/or post-natal treatment with an inverse agonist will improve bone growth. We also propose developing transgenic mice expressing the mutant PTH1R in proximal and distal tubules, and if necessary a ?knock-in? JMC mouse, i.e. a murine model mimicking all disease aspects. Besides correction of growth plate abnormalities in children affected by JMC, it is conceivable that inverse agonists will prevent hypercalcemia and hypercalciuria in pediatric and adult patients with activating PTH1R mutations, and thus nephrocalcinosis and CKD. Insights into the mechanisms that reduce signaling at the mutant PTH1R may lead to effective approaches targeting the wild-type PTH1R through additional peptide analogs or small molecules in patients with PTH- or PTHrP- dependent hypercalcemia, or with secondary hyperparathyroidism due to CKD. In addition, our studies will provide novel insights into growth plate, bone, and kidney physiology, and they will encourage searches for inverse agonists at other disease-causing G protein-coupled receptor mutants.
Jansen's Metaphyseal Chondrodysplasia (JMC) is a rare disorder characterized by hypercalcemia and nephrocalcinosis, and by severe, crippling bone deformities and dwarfism. The constitutive activity of mutant PTH/PTHrP receptors (PTH1R) causing this disease can be reduced in vitro and in vivo through inverse PTH agonists thereby improving bone turnover, chondrocyte differentiation, and growth in transgenic mice expressing the most frequent, JMC-causing PTH1R mutation.
| Saito, Hiroshi; Noda, Hiroshi; Gatault, Philippe et al. (2018) Progression of Mineral Ion Abnormalities in Patients With Jansen Metaphyseal Chondrodysplasia. J Clin Endocrinol Metab 103:2660-2669 |
