Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1-Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism.
Secondary hyperparathyroidism is characterized by increased serum parathyroid hormone (PTH) level and parathyroid cell proliferation. However, the molecular pathways mediating the increased parathyroid cell proliferation remain undefined. Here, we found that the mTOR pathway was activated in the parathyroid of rats with secondary hyperparathyroidism induced by either chronic hypocalcemia or uremia, which was measured by increased phosphorylation of ribosomal protein S6 (rpS6), a downstream target of the mTOR pathway. This activation correlated with increased parathyroid cell proliferation. Inhibition of mTOR complex 1 by rapamycin decreased or prevented parathyroid cell proliferation in secondary hyperparathyroidism rats and in vitro in uremic rat parathyroid glands in organ culture. Knockin rpS6(p-/-) mice, in which rpS6 cannot be phosphorylated because of substitution of all five phosphorylatable serines with alanines, had impaired PTH secretion after experimental uremia- or folic acid-induced AKI. Uremic rpS6(p-/-) mice had no increase in parathyroid cell proliferation compared with a marked increase in uremic wild-type mice. These results underscore the importance of mTOR activation and rpS6 phosphorylation for the pathogenesis of secondary hyperparathyroidism and indicate that mTORC1 is a significant regulator of parathyroid cell proliferation through rpS6.
Department of Nephrology, Hadassah-Hebrew University Medical Center, and.
Oded
O
Volovelsky
Department of Nephrology, Hadassah-Hebrew University Medical Center, and.
Gili
G
Cohen
Department of Nephrology, Hadassah-Hebrew University Medical Center, and.
Ariel
A
Kenig
Department of Nephrology, Hadassah-Hebrew University Medical Center, and.
Gilad
G
Wasserman
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Avigail
A
Dreazen
Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Oded
O
Meyuhas
Department of Nephrology, Hadassah-Hebrew University Medical Center, and.
Justin
J
Silver
Department of Nephrology, Hadassah-Hebrew University Medical Center, and tally@cc.huji.ac.il.
Tally
T
Naveh-Many
D000818:Animals; D049109:Cell Proliferation; D006962:Hyperparathyroidism, Secondary / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000502:physiology*; D010280:Parathyroid Glands / Q000473:pathology*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D038601:Ribosomal Protein S6 / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
D046912:Multiprotein Complexes; D038601:Ribosomal Protein S6; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
calcium-sensing receptor; chronic renal failure; mineral metabolism; parathyroid hormone