By utilising optogenetics, this team of researchers demonstrate a way to control parathyroid hormone secretion to prevent bone loss.
The parathyroid hormone (PTH) is a peptide hormone involved in regulating calcium levels in humans. It plays an important role in phosphorus homeostasis and bone metabolism. The regulation of PTH secretion is mediated by calcium-sensing receptors (CaSRs) on parathyroid cells.
In the development of secondary hyperparathyroidism (SHPT), the expression of CaSRs in the parathyroid gland decreases, leading to persistent secretion of PTH and higher serum PTH levels. With an excess of PTH, bone loss, emotional abnormalities, and hypercalcemia can result. Traditional treatments like parathyroidectomy and calcium mimics cannot recover the rhythmic secretion of PTH. As a result, PTH cannot be physiologically regulated.
Now, researchers led by Professor Yang Fan from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences and their collaborators have put forth a new approach to control parathyroid hormone secretion to prevent SHPT-associated bone loss.
Optogenetics is a biological technique that uses light to control neuronal activity and cellular processes. As this technique has previously been used to control the activity of gonadotropin-releasing hormone neurons and the secretion of lutenising hormone, the researchers hypothesised that optogenetic technology could potentially regulate the secretion of parathyroid hormones as well.
In this study, the research team utilised optogenetic tools to look into the effects and mechanisms behind the optical activation of human parathyroid cells. With their optogenetic approach, they bypassed CaSR and inhibited PTH secretion in both cell/organoid culture models and in situ/transplant animal models. This approach partially attenuated SHPT-associated bone loss.
“The reason for the continuous high-level secretion of PTH in SHPT is that the expression of CaSR in the chief cells decreases, and the membrane potential and intracellular calcium response decrease in the challenge of extracellular calcium stimulation,” said Prof. Yang.
The team found that light stimulation could induce membrane potential changes and intracellular calcium responses as well as inhibit PTH secretion.
The researchers also developed a calcium-response automatic light-regulation system, where a calcium electrode is used to detect changes in extracellular calcium concentration and control light stimulation. When calcium levels reached a certain level, blue light is automatically turned on and PTH levels decreased after light stimulation. However, when calcium levels fell below a certain level, blue light is turned off automatically and there is no difference in PTH levels between parathyroid cells with engineered opsin genes and the control. This demonstrates how an automatic system can help parathyroid cells automatically respond to changes in extracellular calcium concentration so as to moderate PTH levels.
“Most interestingly, the chronic and rhythmic inhibition of PTH induced by optogenetics altered trabecular bone formation and influenced the bone remodelling process, thus partially attenuating bone loss induced by parathyroid gland transplantation in mice,” said Prof. Yang.
The team’s work provides a strategy to regulate the parathyroid and restore human PTH release in secondary hyperparathyroidism, highlighting the potential of optogenetics for the treatment of hyperparathyroidism-induced bone loss.
Source: Liu et al. (2022). An optogenetic approach for regulating human parathyroid hormone secretion. Nature communications, 13(1), 1-17.