Bidirectional Control of Parathyroid Hormone and Bone Mass by Subfornical Organ

Abstract

Parathyroid hormone (PTH) is one of the most important hormones responsible for bone turnover and calcium homeostasis. In mammals, PTH is secreted through the parathyroid glands, unlike in fishes, which are secreted through central nervous system. Studies indicated that a variety of peripheral nerve regulates serum PTH level, however, the mechanism underlying central neural regulation of PTH in mammals remains largely unknown. With an approach including neural-specific retrograde tracing, PTH-Biotin binding assay, and cFos staining, we identified the subfornical organ (SFO) and the paraventricular nucleus (PVN) as two important brain nuclei that responded to serum PTH and calcium changes. Using chemogenetics, we found that serum PTH was suppressed by stimulation of GABAergic neurons in SFO followed by a decrease in trabecular bone mass. Conversely, stimulation of glutamatergic neurons in SFO promoted serum PTH and bone mass. Moreover, we found that the majority of neurons expressing parathyroid hormone 1 receptor (PTH1R) were GABAergic neurons and the majority of neurons expressing parathyroid hormone 2 receptor (PTH2R) were glutamatergic neurons. The paraventricular nucleus (PVN) is downstream of the SFO, and chemogenetic activation of glutamatergic neurons in PVN induced an increase in serum PTH. In summary, our study demonstrates for the first time that distinct neuronal subtypes in the SFO are responsible for bidirectional regulation of serum PTH and bone metabolism, which is mediated through the PVN and the peripheral nervous system. These findings reveal important central neural nodes and will advance our understanding of the central neural regulation of PTH at the molecular, cellular and circuit level.