Molecular characterization of normal and physiologically suppressed human parathyroid glands at single-cell...

Primary hyperparathyroidism (PHPT) is a common endocrine neoplastic disorder caused by excessive parathyroid hormone (PTH) secretion, predominantly due to single gland adenomas that arise in 1 of the 4 parathyroid glands. In the presence of a dominant hypersecretory adenoma, the remaining normal glands become functionally suppressed with attenuated PTH output. The mechanisms underlying suppression remain poorly understood. We performed single-nucleus RNA sequencing combined with immunofluorescence analysis to compare normal and suppressed human parathyroid glands. Transcriptomic analysis of 1.7 billion reads from 83 693 nuclei revealed 4 distinct parathyroid cell populations, including a PDE10A⁺ subtype markedly enriched in suppressed glands and a REXO5⁺ subtype present only in unsuppressed tissue. In suppressed glands, the scavenger receptor LRP2 (Megalin) was strongly up-regulated. Ex vivo treatment of parathyroid glands with an inactivating LRP2 antibody increased PTH secretion, consistent with relief of physiological suppression. Suppressed parathyroid glands internalized extracellular, fluorescently labeled synthetic PTH, an activity blocked by a specific LRP2 antagonist. In parallel, suppression coincided with an increase in PDE10A+ cells and a concomitant reduction in cells expressing PDE11A. PDE11 and PDE10 inhibition selectively enhanced PTH secretion in normal and suppressed glands, respectively. These data suggest that physiological suppression of PTH secretion in normal tissue may be achieved through extracellular PTH scavenging in concert with modulation of intracellular signaling via PDE isoform switching.