Here we explored whether one such inverse agonist ligand, [Leu<sup>11</sup> ,dTrp<sup>12</sup> ,Trp<sup>23</sup> ,Tyr<sup>36</sup> ]-PTHrP(7-36)NH<sub>2</sub> (IA), can be effective in vivo and thus ameliorate the skeletal abnormalities that occur in transgenic mice expressing the PTHR1-H223R allele of JMC in osteoblastic cells via the collagen-1α1 promoter (C1HR mice).
Our findings extend previous reports indicating that PTHrP haploinsufficiency causes skeletal abnormalities similar to those observed with heterozygous GNAS mutations.
The analysis of genetically altered mice which lack either PTHrP or the PTH/PTHrP receptor, as well as of transgenic mice in which the mutant receptor is targeted to the growth plate, has provided a molecular explanation for the severe skeletal abnormalities seen in JMC.
In view of the known role played by the PTH/PTHrP receptor in bone and cartilage development, these results strongly support the conclusion that the absence of functional PTH/ PTHrP receptors is responsible for the skeletal abnormalities seen in Blomstrand chondrodysplasia, abnormalities that are the mirror image of those observed in Jansen's chondrodysplasia.