Phosphorylation of Ribosomal Protein S6 Mediates Mammalian Target of Rapamycin Complex 1–Induced Parathyroid Cell Proliferation in Secondary Hyperparathyroidism

Abstract

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 p2/2 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 p2/2 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. Secondary hyperparathyroidism (SHP) is a major complication of CKD and characterized by increases in parathyroid hormone (PTH) expression and parathyroid cell proliferation. 1-5 Decreased expression of the calcium, vitamin D, and fibroblast growth factor-23 receptors contributes to the increased parathyroid proliferation in uremia. [6][7][8][9][10][11] Expression of TGF-a and its receptor, EGF receptor (EGFR), is increased in uremic rats and patients. 12-14 TGF-a activation of EGFR decreases the CCAAT/ enhancer-binding protein-b liver-enriched activator protein:liver-enriched inhibitory protein, inducing parathyroid growth in uremia. A dominant negative EGFR gene expressed specifically in the parathyroid glands prevented the activation of endogenous EGFR and the increase in parathyroid gland enlargement and serum PTH. 15,16 Parathyroid cell proliferation is increased in transgenic mice overexpressing cyclin D1 only in the parathyroid. 17 The mammalian target of rapamycin (mTOR) integrates signaling pathways to regulate cell growth

Interleukin-6 contributes to the increase in fibroblast growth factor 23 expression in acute and chronic kidney disease

“…IL-6 -/and wt mice were fed an adenine-high-phosphorus diet (TD 140214; Envigo, Somerset, NJ) for 20 days, with a 3-day interval of 0.2% adenine-highphosphorus diet. 40,51 Hydrodynamic, high-pressure, tail-vein injection of plasmids for human a 1-antitrypsin-IL-6 and human a 1-antitrypsin-HIL-6 that contained the HIL-6 fusion protein was performed. Serum was collected at 17 hours.…”

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease

“…Inhibition of mTORC1 by rapamycin both prevented and decreased parathyroid cell proliferation in SHP rats and in vitro in uremic rat parathyroid glands in organ culture. Moreover, knock-in rpS6p −/− mice had impaired PTH secretion in experimental CKD and no increase in parathyroid cell proliferation compared with the expected increase in uremic wild-type mice [ 88 ]. These results highlight the essential role of mTORC1 activation by rpS6 phosphorylation in parathyroid cell proliferation and in the pathogenesis of SHP.…”

“…), the dashed line indicates the suggested effect of MAPK on mTORC1 in the parathyroid cell. Adapted with permission from the Journal of the American Society of Nephrology [ 88 ].…”

Proteome-Wide Effect of 17-β-Estradiol and Lipoxin A4 in an Endometriotic Epithelial Cell Line

“…While its precise function is currently under investigation, studies have shown that RPS6 is involved in the regulation of cell size, cell proliferation, and glucose homeostasis ( 42 ). RPS6 has been implicated in mTOR signaling in hormone responsive cells ( 43 , 44 ). Of note, E2 has been shown to trigger protein synthesis in mouse uterine epithelial cells via the PKC-ERK1/2–mTOR pathway ( 45 ).…”