Precise regulation of parapthyroid hormone secretion with neural modulatory technology

Abstract

Parathyroid hormone (PTH) is one of the most important humoral regulators of extracellular calcium and phosphorus level and exerts profound effects on skeletal homeostasis. Secondary hyperparathyroidism (sHPT) as a common complication associated with 50% of stage 5D chronic kidney disease has received considerable attention. The current medical intervention strategies involve phosphate blocker and calcium mimetic compounds to eliminate the excess phosphate and promote the calcium sensitivity. However, the development of parathyroid gland (PTG) hyperplasia could barely be controlled by medical intervention because of the malfunction of calcium sensory receptor on the surface of hyperplasia PTG. Parathyroidectomy (PTX) surgery with autotransplantation is the only efficient process for the management of severe HPT, which is still followed by problems including lack of response to serum calcium and recurrence. There requires an efficient and reversible strategy that could inhibit the PTH secretion in the hyperplasia glands. Optogenetics is a technology widely applied in neuromodulation which regulates the electric transduction with cell type specificity in an acute and reversible matter. The purpose of the thesis was to define the efficiency of optogenetics regulating parathyroid glands in situ, determine the strategy optogenetics regulating parathyroid transplantation grafts, and to explore II the effect and mechanism on bone remodeling under chronic optogenetic regulation. Primarily, we have demonstrated that optogenetic stimulation of cultured parathyroid cells induces intracellular calcium influx, which initiates the PLC pathway and leads to decreased PTH secretion. Furthermore, in this study, we observed that serum PTH can be reversibly suppressed by optogenetic activation in parathyroid glands of sHPT rat. Enhanced bone formation was observed during the intermittent optogenetic inhibition of exogeneous parathyroid transplants on mice, which was associated with elevated serum osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANKL). On the other hand, nervous system (neural fibers and neuropeptide) plays important role regulating PTH secretion. However, the specific brain areas in central nervous system involved in PTH regulation remain elusive. Through neural specific retrograde tracing and neural activity study, we have identified the brain nuclei associated with PTH with physical and functional connections. Among the PTH-related brain nuclei, we have focused on subfornical organ (SFO), which have abundant expression of PTH receptors and received binding from exogeneous human PTH (1-34), and modulated its neural activity through chemogenetic and optogenetic approaches. Chemogenetic stimulation of GABAergic neuron in SFO resulted in decreased serum PTH and bone resorption while stimulation of glutamatergic neurons in SFO promotes serum PTH and bone reformation. These finds suggest an intricate interplay of different neurons subtypes in precise regulation of PTH release. Taken together, direct application of optogenetics in parathyroid glands provides non-invasive and reversible regulation of PTH secretion in situ and in transplantation grafts. Chemogenetic regulation of GABAergic or glutamatergic neurons of SFO in brain results in promotion and inhibition of serum PTH and influence of bone remodeling. In summary, our study provides potential regulatory strategy to precisely manage PTH secretion through neural modulatory technologies.