Abstract: TH-PO1054

Functional Analysis of Gcm2 in Adult Gcm2 Conditional Knockout Mice

Session Information

Category: Mineral Disease

  • 1201 Mineral Disease: Ca/Mg/PO4

Authors

  • Taku, Yamada, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
  • Tatsumi, Norifumi, Jikei University School of Medicine, Tokyo, Japan
  • Kamejima, Sahoko, Jikei University School of Medicine, Tokyo, Japan
  • Uchiyama, Taketo, Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
  • Ohkido, Ichiro, Division of Nephrology and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan
  • Okabe, Masataka, The Jikei University School of Medicine, Tokyo, Japan
  • Yokoo, Takashi, The Jikei University School of Medicine, Tokyo, Japan
Background

Glial cells missing-2 (Gcm2) is exclusively expressed in the parathyroid gland (PTG). The specific role of mice Gcm2 in the development of PTG from the third pharyngeal pouch has been further investigated, although its function in adult mice remains largely unknown. Gcm2 directly regulates calcium-sensing receptor (CaSR) and transactivates it through Gcm2 response elements in the CaSR promoter, which has important implications for the exacerbation of CKD-MBD. Accordingly, it is possible that Gcm2 plays a crucial role in CKD-MBD and particularly, in secondary hyperparathyroidism (SHPT).

Methods

We generated Gcm2 conditional knockout mice in which loxP sites flanked exons 2 and 3 in the Gcm2 allele. We then crossed these mice with tamoxifen-inducible Cre strain. Next, we intraperitoneally injected 40 mg/kg of tamoxifen into 8-week-old mice for five days. The mice were sacrificed one (1KOmice) and seven (7KOmice) months after tamoxifen administration. We then investigated their serum biochemistry and performed histological analysis.

Results

Serum biochemical parameters of 1KOmice were not significantly different when compared with those of control mice. However, compared with control mice, a significant increase in the serum phosphate level and significant decrease in calcium and parathyroid hormone levels were confirmed in the 1KOmice. Staining of PTG with HE showed that normal structure was generally conserved in 1KOmice, except for the presence of a few follicles, whereas normal structure was not conserved in 7KO mice and their PTGs showed many follicles.

Conclusion

7KOmice showed hypocalcemia, hyperphosphatemia, low parathyroid hormone level, and many follicles in PTG. In addition, normal PTG structure was not observed in these mice. These results suggest that the loss of function of Gcm2 at an adult age leads to hypoparathyroidism, as observed in congenital Gcm2 knockout mice. This animal model is useful to study distinct roles of Gcm2 at different ages and the relationship between Gcm2 and CKD-MBD, particularly SHPT.

Funding

  • Private Foundation Support