Abstract
Secondary hyperparathyroidism (SHP) is a common complication of chronic kidney disease (CKD) that correlates with morbidity and mortality in uremic patients. It is characterized by high serum parathyroid hormone (PTH) levels and impaired bone and mineral metabolism. The main mechanisms underlying SHP are increased PTH biosynthesis and secretion as well as increased glandular mass. The mechanisms leading to parathyroid cell proliferation in SHP are not fully understood. Reduced expressions of the receptors for calcium and vitamin D contribute to the disinhibition of parathyroid cell proliferation. Activation of transforming growth factor-α-epidermal growth factor receptor (TGF-α-EGFR), nuclear factor kappa B (NF-kB), and cyclooxygenase 2- prostaglandin E2 (Cox2-PGE2) signaling all correlate with parathyroid cell proliferation, underlining their roles in the development of SHP. In addition, the mammalian target of rapamycin (mTOR) pathway is activated in parathyroid glands of experimental SHP rats. Inhibition of mTOR by rapamycin prevents and corrects the increased parathyroid cell proliferation of SHP. Mice with parathyroid-specific deletion of all miRNAs have a muted increase in serum PTH and fail to increase parathyroid cell proliferation when challenged by CKD, suggesting that miRNA is also necessary for the development of SHP. This review summarizes the current knowledge on the mechanisms of parathyroid cell proliferation in SHP.
Highlights
Calcium is the major regulator of parathyroid function
parathyroid hormone (PTH) synthesis, secretion, and proliferation are controlled by serum phosphate, vitamin D, and the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) [3,5,6,7,8,9,10]
PTH is a major stimulator of vitamin D activation to 1,25-dihydroxyvitamin D (1,25D) in the kidney. 1,25D, in turn, exerts negative feedback to downregulate the expression of PTH. 1,25D binds to the vitamin D receptor that forms a heterodimer with retinoic X receptor on vitamin D response elements in the PTH gene promoter [16,17,18]
Summary
Calcium is the major regulator of parathyroid function. The parathyroid calcium-sensing receptor (CaSR), a 7-transmembrane G-protein-coupled receptor located on the parathyroid cell membrane, senses small changes in serum calcium [1]. SHP of 5/6 nephrectomized rats is characterized by an increase in serum and PTH mRNA levels and parathyroid cell proliferation that are further increased when the nephrectomized rats are fed a high-phosphorus diet. The tight control of calcium homeostasis is interrupted in patients with either primary or secondary hyperparathyroidism caused by end-stage renal disease This abnormal control of PTH secretion is attributed, at least in part, to the downregulation of the CaSR in hyperplastic parathyroid tissue. Similar findings were observed i arathyroid glands of dietary adenine high-phosphorus CKD models [46] This process apparentl curs only after the development of parathyroid hyperplasia and is enhanced by high phosphat take [52,53]. Vitamin D-supplemented diet in SHP rat models increased the expression of the VDR and CaSR and therefor reduced parathyroid cell proliferation [59,60]. They correct the reduced vitamin D receptor expression of SHP [64]
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