Innovative Mouse Model to Study Parathyroids and an Application to Human Disease

Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Parathyroid glands produce parathyroid hormone (PTH), one of the most important regulators of calcium and phosphate homeostasis, and of bone metabolism. FGF23, secreted from bone, is another crucial regulator of phosphate homeostasis. Recent data have suggested a bone-parathyroid axis in which FGF23 and PTH regulate each other; however, the existing data are contradictory and require clarification. Progress in understanding the molecular regulation of parathyroid cells is very slow because no cell line exists, the glands are very small, and in vivo molecular analysis is almost impossible. Since dysfunction of the parathyroid gland leads to severe consequences such as soft-tissue calcification, fragile bones, chronic renal failure, myopathy, cardiac dysfunction, hematological abnormalities, rickets, and osteomalacia, a new approach is needed to address this question.

The overall goal of this proposal is to generate an innovative and unique mouse model with a retroviral receptor stably expressed on the surface of parathyroid cells. This mouse can then be induced to express different genes including siRNAs exclusively in the parathyroid glands through simple intraperitoneal injection of retroviral constructs. Targeting different genes alone or in combination to the parathyroids is then possible without the need to generate new transgenic mice for each construct. We will also apply this new model to a specific genetic form of hypoparathyroidism (HP). Novel heterozygous mutations in GCMB were identified in two families with a genetic, autosomal dominant form of hypoparathyroidism that have a dominant-negative effect (dnGCMB). We will express either wild type or dnGCMB in the parathyroids to identify its role in postnatal parathyroid glands.

Understanding the actions of GCMB might help in the development of therapeutic agents affecting parathyroid gland function and thus could be used for a wide range of diseases, including primary hyperparathyroidism, a much more common disorder than HP, and secondary hyperparathyroidism related to chronic kidney disease. This innovative in vivo model will not only help us understand the regulatory network in the parathyroid glands but will serve as a useful model for similar research in other systems.