Abstract
Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of calcium-sensing receptors (CaSR) in the parathyroid gland decreases, which leads to persistent hypersecretion of PTH. How to precisely manipulate PTH secretion in parathyroid tissue and underlying molecular mechanism is not clear. Here, we establish an optogenetic approach that bypasses CaSR to inhibit PTH secretion in human hyperplastic parathyroid cells. We found that optogenetic stimulation elevates intracellular calcium, inhibits both PTH synthesis and secretion in human parathyroid cells. Long-term pulsatile PTH secretion induced by light stimulation prevented hyperplastic parathyroid tissue-induced bone loss by influencing the bone remodeling in mice. The effects are mediated by light stimulation of opsin expressing parathyroid cells and other type of cells in parathyroid tissue. Our study provides a strategy to regulate release of PTH and associated bone loss of SHPT through an optogenetic approach.
Highlights
Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis
Immunofluorescent staining of the cultured cells revealed that most of the isolated cells expressed parathyroid hormone (PTH), calcium-sensing receptors (CaSR) and Vitamin D receptors (VDR) (Fig. 1c), and there were few signals in the negative control group and the adjacent thyroid gland tissue (Supplementary Fig. 1c, d)
We found that optical stimulation of secondary hyperparathyroidism (SHPT)-patientderived parathyroid cells can induce inhibition of human PTH
Summary
Parathyroid hormone (PTH) plays crucial role in maintaining calcium and phosphorus homeostasis. In the progression of secondary hyperparathyroidism (SHPT), expression of calcium-sensing receptors (CaSR) in the parathyroid gland decreases, which leads to persistent hypersecretion of PTH. We establish an optogenetic approach that bypasses CaSR to inhibit PTH secretion in human hyperplastic parathyroid cells. We found that optogenetic stimulation elevates intracellular calcium, inhibits both PTH synthesis and secretion in human parathyroid cells. The parathyroid gland (PTG) secrets PTH to regulate serum calcium, which effects bone, kidney, and the intestines. In the progression of secondary hyperparathyroidism (SHPT), the expression of CaSR in the parathyroid gland decreases and limits the regulation of PTH secretion based on calcium levels[6]. Light activation of the parathyroid inhibits human PTH secretion by depolarizing the membrane potential, elevating intracellular calcium, and modulating cell signaling pathways. The in vivo long-term inhibition of human PTH secretion can substantially enhance bone formation and repress bone reabsorption by influencing the bone remodeling process
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