Abstract: TH-OR35
The Essential Roles of miRNA and mTORC1 in Parathyroid Function and in Maintaining Parathyroid Glands in the Adult
Session Information
- Research Advances in Bone and Mineral Metabolism
November 02, 2023 | Location: Room 111, Pennsylvania Convention Center
Abstract Time: 05:06 PM - 05:15 PM
Category: Bone and Mineral Metabolism
- 501 Bone and Mineral Metabolism: Basic
Authors
- Hassan, Alia, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- Khalaily, Nareman, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- Levin, Rachel, Jerusalem Collage of Technology Lev Institute, Jerusalem, Israel
- Volovelsky, Oded, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- Nechama, Morris, Hadassah Hebrew University Medical Center, Jerusalem, Israel
- Ben-Dov, Iddo Z., Hadassah Hebrew University Medical Center, Jerusalem, Israel
- Naveh-Many, Tally, Hadassah Hebrew University Medical Center, Jerusalem, Israel
Background
Secondary hyperparathyroidism (SHP) of CKD is a leading cause of morbidity and mortality. The molecular mechanisms governing basal PTH levels and SHP are undefined. We have shown that the parathyroid mTORC1 pathway is activated in CKD-SHP and that ablation of the miRNA processing enzyme Dicer and hence miRNA prevents CKD-SHP with no effect on basal serum PTH.
Methods
We generated mice with parathyroid (PT) specific KO of Dicer, mtorc1, tuberous sclerosis complex 1 (Tsc1) or double Dicer-/- ;Tsc1-/- KO and tdTomato expression to identify the glands by fluorescent microscopy. Parathyroid sections were IF stained.
Results
Despite normal serum PTH, adult PT-Dicer-/- mice had no intact parathyroid glands, unlike controls. The glands were present at birth but soon after only clumps of parathyroid cells remained, indicating that Dicer and miRNA are not essential for parathyroid embryogenesis but rather for maintaining intact glands later in life. To characterize a miRNA-mTORC1 link in the parathyroid, we generated PT-mTORC1-/- mice that had parathyroid cell clumps from early after birth but normal serum PTH, resembling PT-Dicer-/- mice. In contrast, PT-Tsc1-/- mice with mTORC1 hyper-activation due to deletion of its inhibitor, had vastly larger (x10) glands and increased serum PTH and calcium levels. IF staining for parathyroid specific and proliferation markers supported the KO phenotypes. Importantly, a double PT-Dicer-/- ;Tsc1-/- mouse had intact parathyroid glands similar to controls, indicating that Tsc1 ablation over-rides the aparathyoridism of Dicer KO.
Conclusion
miRNAs are essential for PTH stimulation in CKD induced SHP. Both miRNA and mTORC1 maintain intact glands in the adult.