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

Abstract

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 of Dicer and consequently microRNA, maintained normal serum PTH levels but failed to increase serum PTH in response to the major inducers of PTH secretion, hypocalcemia and CKD. 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 sustaining normal serum PTH levels, PT-Dicer-/- mice displayed apoptotic loss of intact parathyroid glands postnatally, which were replaced by scattered cell clusters, and reduced mTORC1 activity. PT-mTORC1-/- mice exhibited the absence of intact parathyroid glands, while retaining normal serum PTH levels, mirroring the characteristics of PT-Dicer-/- mice. Conversely, PT-Tsc1-/-mice with hyperactivated mTORC1 exhibited enlarged glands and elevated serum PTH and calcium levels. Significantly, PT-Dicer-/-;Tsc1-/- double knockout mice demonstrated a reversal of the aparathyroidism of PT-Dicer-/- mice, preserving intact parathyroid glands and reinstating CKD-induced SHP. Lastly, data collected from a network of 106 healthcare organizations demonstrated that drug-induced mTOR inhibition is associated with reduced elevation of serum PTH levels in kidney transplant recipients. The latter findings offer physiological validation for our observations in genetically modified mouse models, highlighting the central role of mTORC1 signaling in CKD-SHP. Altogether, our results indicate that mTOR operates downstream of Dicer and miRNA. Consequently, Dicer, miRNA and mTORC1 collectively play a crucial role in maintaining the postnatal integrity and function of the parathyroid glands.