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Abstract: TH-PO532

An Internal Molecular Circadian Clock Operates in the Parathyroid Gland and Is Disturbed in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Egstrand, Søren, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
  • Nordholm, Anders, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
  • Mace, Maria Lerche, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
  • Morevati, Marya, Dept. of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Olgaard, Klaus, Dept. of Nephrology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
  • Lewin, Ewa, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
Background

Parathyroid hormone (PTH) secretion exhibits a well-known circadian rhythmicity (CR) which is disturbed in secondary hyperparathyroidism (sHPT). The mechanism behind the CR of PTH is, however, unknown and not correlated to the CRs of calcium (Ca) and phosphate (P). Furthermore, the parathyroid gland is not controlled by a superior “hypothalamic-pituitary axis”. The possible existence of a molecular circadian clock in the parathyroid cell has not previously been examined.

Methods

Normal male Wistar rats were kept in 12h:12h light:dark cycle and fed ad libitum. Parathyroid glands were harvested with 4 hours interval for 24 hours, along with plasma samples for PTH (pg/ml), P (mM), total Calcium (mM), Urea (mM) and Creatinine (µM). (N=38; 6 per timepoint). Gene expression was examined by qPCR analysis. sHPT was induced by 5/6 nephrectomy and high phosphorus diet for 24 weeks. (N=10 and 16 age-matched controls).

Results

Parathyroid glands showed clear expression of core molecular clock genes: Bmal1, Clock, Per1-3, Cry1-2 and Rev-Erbα. The circadian rhythmicity was examined by cosinor analysis fitted to a period of 24h and was significant for Bmal1 (p<0.0001), Per2 (p<0.0001), Per3 (p<0.0001), Cry1 (p<0.0001), Cry2 (p=0.002) and Rev-Erbα (p<0.0001). Significant rhythmicity was also found for the cell cycle gene Cyclin D1 (p=0.003).
In parathyroid glands from uremic rats, downregulation of Clock (1.61±0.38 vs. 4.19±1.21, p=0.041) was found, as well as circadian clock output gene CSNK1ε (1.05±0.24 vs. 2.27±0.34, p=0.047). Also cell cycle gene Cyclin D1 was downregulated in uremic rats (1.20±0.24 vs. 3.36±0.73, p=0.041).

Conclusion

The existence of a parathyroid molecular circadian clock is demonstrated for the first time. The expression of the parathyroid circadian clock genes is disturbed in uremic parathyroid glands, which potentially can contribute to the disturbed circadian rhythmicity of circulating PTH and to the development of parathyroid hyperplasia in uremia.