Dicer-Mediated mTORC1 Signaling and Parathyroid Gland Integrity and Function

Abstract

Key Points Maintaining parathyroid gland integrity is a dynamic process regulated by the parathyroid microRNA–mechanistic target of rapamycin complex 1 axis.This axis is essential for preserving intact parathyroid glands throughout life, with relevance to CKD-induced secondary hyperparathyroidism. Background Secondary hyperparathyroidism of CKD contributes significantly to patient morbidity and mortality. The underlining mechanisms of CKD-induced secondary hyperparathyroidism remain elusive. We previously demonstrated that PT-Dicer −/− mice, with parathyroid-specific deletion of the microRNA (miRNA)-processing enzyme Dicer and consequently miRNA, maintain normal basal serum parathyroid hormone (PTH) levels but do not develop secondary hyperparathyroidism induced by CKD. In addition, we showed that the parathyroid mechanistic target of rapamycin complex 1 (mTORC1) pathway is activated in CKD. We now explored the roles of Dicer/miRNA and mTORC1 in parathyroid development and function. Methods We generated mice with parathyroid-specific Dicer (PT-Dicer −/− ), mechanistic target of rapamycin (PT-mTOR −/− ), or tuberous sclerosis complex 1 (PT-Tsc1 −/− ) deficiency combined with yellow fluorescent protein (YFP) or tdTomato expression to identify the parathyroids by fluorescence microscopy. CKD was induced by an adenine-rich high-phosphate diet. Results Despite normal basal serum PTH levels, PT-Dicer −/− mice displayed apoptotic loss of intact parathyroid glands postnatally and reduced mechanistic target of rapamycin activity. PT-mTOR −/− mice lacked intact parathyroid glands yet maintained normal serum PTH levels, mirroring the phenotype of PT-Dicer −/− mice. Conversely, PT-Tsc1 −/− mice with hyperactivated mTORC1 exhibited enlarged glands along with elevated basal serum PTH and calcium levels. Significantly, PT-Dicer −/− ;Tsc1 −/− double knockout mice preserved intact parathyroid glands and reinstated CKD-induced secondary hyperparathyroidism. Conclusions mTORC1 operates downstream of Dicer and miRNA in the parathyroid and is essential for maintaining postnatal parathyroid gland integrity throughout life and for the pathogenesis of CKD-induced secondary hyperparathyroidism.