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Abstract: TH-PO147

mTOR Activity Is Essential for Intact Parathyroid Gland Structure

Session Information

  • CKD-MBD: Targets and Outcomes
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Khalaily, Nareman, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
  • Hassan, Alia, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
  • Silver, Justin, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
  • Nechama, Morris, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
  • Volovelsky, Oded, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
  • Naveh-Many, Tally, Hadassah University Medical Center, Jerusalem, Jerusalem, Israel
Background

<div style="direction: ltr;">mTOR signaling links nutritional status and cell metabolism and is negatively regulated by tuberous sclerosis complex 1 (TSC1). mTOR is a significant regulator of parathyroid cell proliferation in CKD-induced secondary hyperparathyroidism (SHP). CKD leads to parathyroid mTOR pathway activation and the mTOR inhibitor rapamycin decreases parathyroid cell proliferation in vivo and in organ cultures. We now show that in addition to its roles in SHP-induced parathyroid cell proliferation, the mTOR pathway is central to maintaining intact parathyroid glands in mice with normal renal function.</div>

Methods

<div style="direction: ltr;">We generated by cre-lox recombination mice with parathyroid-specific mTOR deletion or mTOR activation by TSC1 knockout (KO), combined with red fluorescent protein expression, to monitor the parathyroid glands and allow fluorescent guided microdissection. CKD was induced by an adenine high phosphorus diet. Serum PTH, calcium, phosphate, and urea were measured at different time points after birth. Microdissected parathyroid sections were analyzed by immunofluorescent staining.</div>

Results

<div style="direction: ltr;">Parathyroid-specific mTOR KO mice had smaller, punctuated parathyroid glands, from early after birth, with low to normal serum PTH levels. Surprisingly, dietary-induced CKD increased serum PTH to similar levels in both mTOR KO and control mice, despite much smaller still disrupted parathyroid glands in KO mice. In contrast, ablation of the negative mTOR regulator TSC1 led to ~10-fold larger parathyroid glands compared to control mice at 1 month of age. However, serum PTH levels were similar, suggesting that more cells are needed to produce normal serum PTH in TSC1 KO mice. From the age of 2 month, the TSC1 KO mice had ~4-fold higher serum PTH levels and only ~5-fold larger glands compared to controls. CKD similarly increased serum PTH levels in TSC1 KO and control mice, with a reduced fold increase in the KO mice. Immunofluorescent staining for PTH, CaSR, GCM2, phosphorylated ribosomal protein S6, and proliferation markers further supported the phenotype of the mTOR and TSC1 KO mice.</div>

Conclusion

<div style="direction: ltr;">This is the first demonstration that mTOR is central to parathyroid gland morphology and maintaining intact glands in the adult.</div>