A new study shows that increased production of parathyroid hormone (PTH) by the parathyroid glands in response to hypocalcaemia and uraemia is dependent on endonuclease dicer and microRNA (miRNA) maturation. As secondary hyperparathyroidism—the excessive production of PTH in response to hypocalcaemia or uraemia—is a frequent complication of chronic kidney disease, the findings might lead to new strategies for the management of secondary hyperparathyroidism in patients with renal disease.
The researchers, led by Tally Naveh-Many, generated parathyroid-specific Dicer1 knockout (Dicer1PT−/−) mice and subjected them to acute hypocalcaemia (induced by intraperitoneal injection of ethylene glycol tetraacetic acid). Whereas serum levels of PTH increased fivefold in control mice, no increase was observed in Dicer1PT−/− mice, which demonstrates that Dicer1 and Dicer1-dependent miRNAs are essential for the increased PTH secretion induced by acute hypocalcaemia. In vitro culturing of parathyroid gland tissue in a low-calcium medium confirmed the in vivo findings: PTH secretion increased 20-fold in explant cultures from control mice, whereas the response was substantially diminished in those from Dicer1PT−/− mice.
Chronic hypocalcaemia (induced by feeding weanling mice a calcium-depleted diet for 3 weeks) also induced less PTH secretion in Dicer1PT−/− mice than in control mice. Under the same conditions, PTH secretion was also impaired in heterozygous Dicer1PT+/− mice compared with controls, indicating that Dicer1 haploinsufficiency is enough to abrogate the response of the parathyroid glands to hypocalcaemia. Uraemia (induced by feeding mice an adenine high-phosphorus diet) also reduced the PTH response in Dicer1PT−/− mice compared with controls, which indicates that development of secondary hyperparathyroidism due to both uraemia and chronic hypocalcaemia is reliant on Dicer1-dependent miRNAs.
Going forward, the researchers plan to identify the specific miRNAs and their target mRNAs in the parathyroid gland that mediate the increased expression of PTH in secondary hyperparathyroidism and acute hypocalcaemia.
Shilo, V. et al. Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia. FASEB J. 10.1096/fj.15-274191
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Holmes, D. Key role for dicer-dependent miRNAs. Nat Rev Endocrinol 11, 445 (2015). https://doi.org/10.1038/nrendo.2015.104