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Novel Mouse Model Allows Comparison of Candidate Parathyroid Hormone Ligand Analogs

Key findings

  • This paper describes a novel strain of engineered mouse that expresses the human parathyroid hormone 1 receptor (PTH1R) instead of endogenous murine PTH1R
  • Initial functional characterization of baseline and ligand-induced bone and blood calcium ion responses established the viability of the mice
  • A preliminary evaluation showed the mice are a potential test model for predicting the behavior of candidate PTH analogs in humans and could improve the understanding of how PTH1R and its ligands regulate bone biology and mineral ion homeostasis

The parathyroid hormone 1 receptor (PTH1R) is a common drug target for the treatment of osteoporosis and hypoparathyroidism. By mediating the activity of two peptide ligands, PTH and PTH-related protein (PTHrP), it plays critical roles in regulating blood calcium and phosphate (via PTH) and bone and tissue development (via PTHrP).

The PTH1R in humans shares 91% amino acid sequence identity with the PTH1R in rats and mice. Still, the divergence can lead to differences in receptor-binding affinities and signaling potencies when ligands are assessed in rodents versus humans. Those differences introduce an element of uncertainty about how data from rodent studies apply to humans.

To overcome that uncertainty, researchers at Massachusetts General Hospital have engineered "humanized" mice that express human PTH1R instead of the analogous mouse protein. The endogenous mouse promoter directs expression, so PTH1R occurs in all biologically relevant cells and tissues.

Thomas J. Gardella, PhD, an associate investigator in the Endocrine Unit of the Mass General Research Institute, Eileen J. Daley, PhD, a research fellow in the Unit, and colleagues describe the mice in Endocrinology, along with an initial evaluation of their clinical utility.

Characterizations of the Mice

For bone structure and levels of blood markers of bone turnover and mineral ion homeostasis, the homozygous human PTH1R knock-in mice closely resembled wild-type control mice of the same age and genetic background. They were healthy over 10 generations and showed functional responses to injected PTH analog peptides, consistent with a fully functional human PTH1R in target bone and kidney cells.

Utility of the Mice

The researchers hope to use the humanized mice to assess new PTH analogs in vivo. As a first step, they examined humanized and wild-type mice before and at various times after single subcutaneous injection of:

  • Teriparatide, also known as PTH(1-34)
  • PTHrP(1-36)
  • Abaloparatide, an analog of PTHrP(1-34)

Teriparatide and abaloparatide are FDA-approved bone anabolic treatments for osteoporosis.

In the humanized mice, teriparatide induced more prolonged calcemic and phosphaturic responses than either of the other two ligands, and this difference in response duration was not evident in the wild-type mice.

Implications for Drug Development

The humanized mice offer advantages over conventional rodent models for functionally differentiating between structurally distinct PTH and PTHrP ligand analogs in vivo. The mouse model could be used to complement various molecular and cellular tools in predicting the efficacy of a new PTH or PTHrP ligand analog in treating diseases of bone and mineral ion metabolism in humans.

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