Discovery may tame overactive parathyroid glands

The discovery of a protein that appears to protect parathyroid glands from overactivity may lead to new drugs to treat hyperparathyroidism.

The condition is currently treatable only with surgery.

The parathyroid are four small glands located in the neck, behind the larger thyroid, and are responsible for maintaining healthy blood calcium levels through the secretion of parathyroid hormone (PTH).

Overactive parathyroid glands, which control the body’s blood calcium levels, can lead to kidney stones, neuropsychiatric disorders, and bone abnormalities, particularly among elderly women. The condition is called primary hyperparathyroidism.

“Not many molecules are known to inhibit parathyroid growth and there are no drugs available in the market to treat the condition,” says Manvendra Singh, assistant professor in the cardiovascular and metabolic disorders program at Duke-NUS Medical School and corresponding author of the study in the Journal of Biological Chemistry.

“Surgery is the most common treatment for hyperparathyroidism. However, reoperative surgery for persistent or recurrent hyperparathyroidism remains technically challenging due to fibrotic scarring and distorted anatomy that make it more difficult to identify abnormal parathyroid glands.”

Researchers discovered that semaphorin3d (Sema3d), a signaling protein secreted by developing parathyroid glands, helps to prevent excessive growth. The protein reduced signaling within the EGFR/ERBB signaling pathway, which is responsible for parathyroid cell growth, and also mediates cancer growth and survival.

In a transgenic model lacking the gene that codes for Sema3d, EGFR signaling activated, leading to parathyroid cell proliferation and the development of primary hyperparathyroidism. Turning off EGFR signaling with a known anti-cancer drug caused some of the parathyroid tissue to return to normal.

The finding suggests Sema3d and drugs that can similarly inhibit EGFR signaling could treat hyperparathyroidism.

“This discovery is a potential game-changer in the treatment of hyperparathyroidism,” says Patrick Casey, professor and senior vice dean for research. “Considering the condition is common in the elderly, possible drug-based therapeutic options in the future would reduce the burden of surgery and associated risks in these elderly patients.”

The research team says they believe Sema3d’s protective role in restricting parathyroid cell proliferation could also be relevant to other tumor types. Further investigations could lead to the development of anti-tumor treatments using genetically engineered Sema3d or other drugs that target the protein’s downstream pathways, the researchers say.

Source: Duke-NUS