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.