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Abstract: TH-OR20

Parathyroid-Specific Knockout of Core Circadian Clock Gene Bmal1 Increases Proliferation of the Parathyroid Gland in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic


  • Egstrand, Søren, Herlev Hospital, Herlev, Denmark
  • Mace, Maria Lerche, Rigshospitalet, Copenhagen, Denmark
  • Morevati, Marya, Rigshospitalet, Copenhagen, Denmark
  • Nordholm, Anders, Herlev Hospital, Herlev, Denmark
  • Olgaard, Klaus, Rigshospitalet, Copenhagen, Denmark
  • Lewin, Ewa, Herlev Hospital, Herlev, Denmark

Proper rhythms in metabolism, hormone secretion and cell cycle are maintained by a molecular circadian clock (CC) in the CNS as well as in peripheral tissues. The transcription factor Bmal1 is a major component of the CC. We have previously shown that an internal CC operates in the parathyroid gland (PTG) and that it is disturbed in uremia. We constructed a PTG-specific Bmal1 knockout mouse to investigate the function of the PTG clock in health and in CKD.


PTG-specific knockout of Bmal1 was generated by crossing PTHcre mice with Bmal1flox/flox mice (WT) giving rise to PTHcre;Bmal1flox/flox (KO). Blood samples and PTGs were harvested at 4h interval. CKD was induced by feeding mice an adenine diet for 3 weeks. Gene expression was examined by qPCR, protein expression by western blot and proliferation by Ki-67 labeling. Circadian rhythmicity was assessed by cosinor analysis.


BMAL1 protein was reduced by 77% in the PTGs of KO mice and circadian rhythmicity of Bmal1 gene expression was abolished along with abolishment of rhythmicity of clock genes Cry1 and Cry2 and significant upregulation of clock genes Per2 (p=0.01), Cry1 (p<0.0001) and Cry2 (p=0.0001), compared to WT. The disturbed clock in KO resulted in abrogated rhythmicity of clock-controlled cell cycle regulator Wee1 (KO p=0.16, WT p=0.0016) and of regulators of parathyroid proliferation Gcm2 (KO p=0.63, WT p=0.03) and Gata3 (KO p=0.84, WT p=0.01). Gata3 was upregulated compared to WT (p=0.01). Plasma PTH was significantly rhythmic in both KO and WT mice. In a basal condition the phenotype of KO mice was similar to WT, regarding weight, femur length, basal PTH levels and secretory response to hypocalcemia.
Uremia significantly increased the PTG KI-67 labeling index in KO compared with WT (7.0% vs. 2.4%, p=0.036).


Bmal1 knockout in the PTG resulted in disrupted rhythm of CC genes and a clock-controlled cell cycle regulator. The significant rhythms of regulators of parathyroid proliferation; Gcm2 and Gata3 found in PTGs of WT mice was absent in KO mice suggesting CC regulation of these genes.
Increased KI-67 expression was found when PTGs of KO mice were challenged by CKD as compared to WT mice, indicating a key role of the CC in regulating the proliferation in the PTGs.