Nancy Manley has a standard joke: parathyroid glands are the Rodney Dangerfields of organs. They get no respect.
They are even named for the organ they lie next to in the body, even though their functions are organically unrelated. These four, rice-sized objects are located behind the thyroid gland where they work for a lifetime controlling the amount of calcium in the body’s blood system.
When things go wrong with the parathyroids, serious problems can result, since calcium provides electrical energy for the nervous and muscular systems and strength for skeletal structure. Despite the importance of the parathyroids, however, parts of the science surrounding their formation and function have remained unclear, such as the full source of the important parathyroid hormone or PTH.
Led by Manley, a UGA professor of genetics and chair of the interdepartmental developmental biology group, scientists have shown for the first time that the thymus, which had been proposed to serve as a “backup” source for parathyroid function, does not contribute to serum PTH levels. They also have demonstrated that “physiologically relevant” thymic PTH comes from multiple small parathyroid clusters that form during the normal process of parathyroid gland development in an embryo.
Together, the two findings, published recently online in the journal PloS Genetics, open the door for a new understanding of the role of these crucial glands in health.
“Many people have been found to have these ‘extra’ parathyroid glands, and before now, there was no clear source of origin for them,” said lead research author Manley. “Due to the important role of PTH in the regulation of physiological activities and associated disease problems it can cause in humans, it is very important to understand where it is produced and how it is regulated. This new research gives us important new clues to how this all works.”
Other authors on the paper were former UGA graduate students Zhijie Liu and Lizhen Chen; Alison Farley and Clare Blackburn of the University of Edinburgh in Scotland; and Beth Kirby and Christopher Kovacs from the Memorial University of Newfoundland in Canada.
Most people probably know something about the thyroid, the butterfly-shaped gland in the throat that controls how quickly the body makes proteins and uses energy. The parathyroid glands, however, primarily regulate calcium levels in the bloodstream through the production of PTH, and their embryonic development is closely linked to that of another important organ, the thymus. While researchers had long thought that the parathyroid glands were the sole source of PTH production and secretion, this developmental link had led, in part, to an earlier conclusion that in the absence of the parathyroid glands, the thymus could act as an auxiliary source for PTH. Since the parathyroid glands are removed surgically to treat certain parathyroid diseases, this finding had important clinical implications.
Instead, according to the Manley team, “thymus-derived” PTH comes from these small clusters of parathyroid cells that develop at the same time the thymus does but get separated from the main parathyroid glands during development.
“Our data reveal two cellular sources of extra-parathyroid PTH,” said Manley. “The first source is these ‘misplaced’ parathyroid cells that arise during normal organ development. The second source is in medullary thymic epithelial cells, or mTECs, but PTH from this source does not appear to have any endocrine function and probably serves as an internal control mechanism called a self-antigen, which is important for preventing autoimmunity.”
The analysis of Farley and Blackburn is also the first genetic marker-study of human parathyroid embryonic development and reveals new information that differs from the original descriptions of development from earlier studies. The research provides insight into understanding some hyperparathyroid disorders caused by these “extra” parathyroid glands.
The location of these extra clusters of glands is so unpredictable, in fact, that their development seems “sloppy,” Manley said, because the cells don’t express high enough levels of adhesion molecules for them to reside in the same place in every body.
“In a sense, they are like endocrine Post-It Notes rather than being attached to each other with super glue,” Manley said.
Complicating the understanding of PTH is the fact that the thymus does produce some PTH, but none of it is secreted into the bloodstream, meaning it has no overall endocrine function.
Understanding the origin of PTH has clinical relevance, since it would be a natural candidate for stem cell therapy, Manley said. Since the parathyroids control the levels of calcium in the blood, they are also important in osteoporosis, and the new knowledge could be useful in finding new therapies for that common disorder.
