The essential roles of Dicer-mediated mTORC1 signaling in parathyroid gland integrity and function: Insights from genetic mouse models and clinical data

Abstract

Parathyroid hormone (PTH) is central for mineral metabolism and bone strength. Secondary hyperparathyroidism (SHP) frequently accompanies chronic kidney disease (CKD), contributing to morbidity and mortality in patients. Our previous findings demonstrated that PT-Dicer-/-mice, with parathyroid specific deletion ofDicerand consequently microRNA, maintained normal serum PTH levels but failed to increase serum PTH in response to hypocalcemia and CKD, the major inducers of PTH secretion. Additionally, we elucidated a critical role of mTORC1 in CKD-induced SHP. We now explored the roles of Dicer and mTORC1 in parathyroid development and function. Despite normal serum PTH levels, PT-Dicer-/-mice displayed apoptotic loss of intact parathyroid glands postnatally, which were subsequently replaced by scattered cell clusters, and reduced mTORC1 activity. Accordingly, PT-mTORC1-/-mice exhibited the absence of intact parathyroid glands, while retaining normal serum PTH levels, similar to PT-Dicer-/-mice. Conversely, PT-Tsc1-/-mice with hyperactivated mTORC1 exhibited enlarged glands and elevated serum PTH and calcium levels. Notably, PT-Dicer-/-;Tsc1-/-double knockout mice demonstrated a reversal of PT-Dicer-/-aparathyroidism, preserving intact parathyroid glands and reinstating CKD-induced SHP. These findings imply that mTOR operates downstream of Dicer and miRNA depletion. Moreover, Dicer, miRNA and mTORC1 are crucial to postnatal parathyroid gland integrity and function.