New regulators of parathyroid hormone secretion

Parathyroid hormone (PTH) regulates mineral metabolism and bone strength. Beyond the well-characterized roles of calcium, phosphate, vitamin D, and fibroblast growth factor 23 (FGF23), emerging evidence identifies leptin as a previously under-recognized parathyroid regulator, Secondary hyperparathyroidism (SHP) is a major complication of chronic kidney disease (CKD) characterized by dysregulated PTH secretion and parathyroid hyperplasia. The intracellular signaling mechanisms driving SHP remain elusive. This review examines the role of leptin in PTH regulation and parathyroid physiology and highlights experimental and clinical evidence identifying mechanistic target of rapamycin complex 1 (mTORC1) as a critical regulator of parathyroid structure and function in CKD-SHP.

Leptin has been shown to directly stimulate PTH secretion, at least in part by downregulating calcium-sensing receptor (CaSR) signaling, establishing a novel leptin-PTH axis. In experimental CKD, uremia triggers robust parathyroid mTORC1 activation, promoting cellular hyperplasia and PTH overproduction both of which are prevented and reversed by rapamycin. Genetic mouse models show that parathyroid-specific mTOR deletion impairs gland integrity and adaptive PTH responses, whereas constitutive mTORC1 activation via Tsc1 deletion induces autonomous gland enlargement and impaired secretory capacity. Clinically, kidney transplant recipients treated with mTOR inhibitors exhibit lower PTH levels and reduced SHP incidence compared to those receiving other immunosuppressants.

mTORC1 is a central integrator of parathyroid growth, structural integrity and hormone secretion. Targeting mTORC1 signaling offers a promising therapeutic strategy for the prevention and management of CKD-associated SHP.