Data for: Actions of Parathyroid hormone ligand analogs in humanized PTH1R knock-in mice

Rodent models are commonly used to evaluate parathyroid hormone (PTH) and PTH-related protein (PTHrP) ligands and analogs for their pharmacologic activities and potential therapeutic utility towards diseases of bone and mineral ion metabolism.  Divergence, however, in the amino acid sequences of rodent and human PTH receptors (rat and mouse PTH1Rs are 91% identical to the human PTH1R) can lead to differences in receptor-binding and signaling potencies for such ligands when assessed on rodent versus human PTH1Rs, as shown by cell-based assays in vitro. This introduces an element of uncertainty in the accuracy of rodent models for performing such pre-clinical evaluations.  To overcome this potential uncertainty, we used a homologous recombination-based knock-in (KI) approach to generate a mouse (in host strain C57Bl/6N) in which cDNA encoding the human PTH1R replaces a segment (Exon 4) of the murine PTH1R gene such that the human and not the mouse PTH1R protein is expressed. Expression is directed by the endogenous mouse promoter and hence occurs in all biologically relevant cells and tissues and at appropriate levels.  The resulting homozygous hPTH1R-KI (humanized) mice were healthy over at least ten generations and showed functional responses to injected PTH analog peptides that are consistent with a fully functional human PTH1R in target bone and kidney cells.  The initial evaluation of these mice and their potential utility for predicting behavior of PTH analogs in humans is reported here.