title: Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia.
abstract: MicroRNAs (miRNAs) down-regulate gene expression and have vital roles in biology but their functions in the parathyroid are unexplored. To study this, we generated parathyroid-specific Dicer1 knockout (PT-Dicer(-/-) ) mice where parathyroid miRNA maturation is blocked. Remarkably, the PT-Dicer(-/-) mice did not increase serum parathyroid hormone (PTH) in response to acute hypocalcemia compared with the >5-fold increase in controls. PT-Dicer(-/-) glands cultured in low-calcium medium secreted 5-fold less PTH at 1.5 h than controls. Chronic hypocalcemia increased serum PTH >4-fold less in PT-Dicer(-/-) mice compared with control mice with no increase in PTH mRNA levels and parathyroid cell proliferation compared with the 2- to 3-fold increase in hypocalcemic controls. Moreover, uremic PT-Dicer(-/-) mice increased serum PTH and FGF23 significantly less than uremic controls. Therefore, stimulation of the parathyroid by both hypocalcemia and uremia is dependent upon intact dicer function and miRNAs. In contrast, the PT-Dicer(-/-) mice responded normally to activation of the parathyroid calcium-sensing receptor (Casr) by both hypercalcemia and a calcimimetic that decreases PTH secretion, demonstrating that they are dicer-independent. Therefore, miRNAs are essential for the response of the parathyroid to both acute and chronic hypocalcemia and uremia, the major stimuli for PTH secretion.
authors.affiliation: *Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Vitali
authors.initials: V
authors.lastname: Shilo
authors.affiliation: *Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Iddo Z
authors.initials: IZ
authors.lastname: Ben-Dov
authors.affiliation: *Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Morris
authors.initials: M
authors.lastname: Nechama
authors.affiliation: *Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Silver
authors.affiliation: *Minerva Center for Calcium and Bone Metabolism, Nephrology Services, Hadassah Hebrew University Medical Center, Jerusalem, Israel; and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA tally@cc.huji.ac.il.
authors.forename: Tally
authors.initials: T
authors.lastname: Naveh-Many
mesh_terms: D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D006996:Hypocalcemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010280:Parathyroid Glands / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000235:genetics / Q000378:metabolism*; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D014511:Uremia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C577923:CASR protein, mouse; C000717428:Fgf23 protein, mouse; D035683:MicroRNAs; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D043562:Receptors, G-Protein-Coupled; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: calcium-sensing receptor; renal failure; secondary hyperparathyroidism