Two postnatal mouse models with Pth1r deletion reproduce limb phenotype for Blomstrand chondrodysplasia

Blomstrand chondrodysplasia (BOCD) is a lethal autosomal recessive disorder characterized by skeletal and facial deformity and caused by loss-of-function variants in the parathyroid hormone 1 receptor gene ( PTH1R ). Because BOCD results in embryonic lethality in humans, animal models are required to investigate the detailed postnatal roles of PTH1R signaling. To date, only one inducible Pth1r -ablation model using the Col2-Cre ERT2 driver has been reported. Here, we generated two additional inducible models, Acan-Cre ERT2 ; Pth1r fl/fl ; Tomato fl/+ and Gli1-Cre ERT2 ; Pth1r fl/fl ; Tomato fl/+ mutants, which drivers have been widely used in skeletal research. Both mutants exhibited dwarfism with shortened femoral and tibial lengths. MicroCT and histological analyses showed that the mutants exhibited epiphyseal dysplasia with increased hypertrophic chondrocytes and loss of normal growth-plate architecture. Lineage tracing by detection of Tomato-positive cells verified that these recombined cells contributed to the phenotypes. In the Acan-Cre ERT2 model, expression of chondrocyte marker genes was reduced in mutant epiphyses. In the Gli1-Cre ERT2 model, complete loss of the growth plate was observed at both a juvenile (4 weeks after induction at P3) and an adult endpoint (12 weeks after induction at P21). Collectively, these results show that our Pth1r deletion models recapitulate key BOCD-like phenotypes and provide complementary tools for studying postnatal PTH1R signaling.