Cyclooxygenase 2 Promotes Parathyroid Hyperplasia in ESRD

Abstract

Hyperplasia of the PTG underlies the secondary hyperparathyroidism (SHPT) observed in CKD, but the mechanism underlying this hyperplasia is incompletely understood. Because aberrant cyclooxygenase 2 (COX2) expression promotes epithelial cell proliferation, we examined the effects of COX2 on the parathyroid gland in uremia. In patients with ESRD who underwent parathyroidectomy, clusters of cells within the parathyroid glands had increased COX2 expression. Some COX2-positive cells exhibited two nuclei, consistent with proliferation. Furthermore, nearly 78% of COX2-positive cells expressed proliferating cell nuclear antigen (PCNA). In the 5/6-nephrectomy rat model, rats fed a high-phosphate diet had significantly higher serum PTH levels and larger parathyroid glands than sham-operated rats. Compared with controls, the parathyroid glands of uremic rats exhibited more PCNA-positive cells and greater COX2 expression in the chief cells. Treatment with COX2 inhibitor celecoxib significantly reduced PCNA expression, attenuated serum PTH levels, and reduced the size of the glands. In conclusion, COX2 promotes the pathogenesis of hyperparathyroidism in ESRD, suggesting that inhibiting the COX2 pathway could be a potential therapeutic target. Secondary hyperparathyroidism (SHPT) is one of the most common abnormalities of mineral metabolism in patients with chronic kidney disease (CKD), characterized by hyperplasia of the parathyroid gland (PTG). 1 It is well documented that increased parathyroid hormone (PTH) contributes to bone disorders and cardiovascular complications of ESRD patients and is associated with the morbidity and mortality of this population. 2,3 Strong evidence indicates that PTG hyperplasia is positively linked to the magnitude of circulating levels of PTH, and the size of the PTG is associated with the controllability of parathyroid function in CKD patients. 4,5 The mechanism underlying PTG hyperplasia is incompletely defined.Under normal conditions, the turnover rate of the PTG is very low, and mitoses are seldom observed. 1,6 However, under certain pathologic conditions such as CKD, hyperphosphatemia, and vitamin D deficiency, increased proliferation of the PTG can be detected. 7,8 In CKD patients, the PTG shows diffuse and polyclonal proliferation at early stages of SHPT. With progression of the disease, the PTG can transform with monoclonal and aggressive proliferation. 9 -11 It is well accepted that PTG hyperplasia is associated with reduced 1,25-vitamin

Association of Circulating Fibroblast Growth Factor-23 with Renal Phosphate Excretion among Hemodialysis Patients with Residual Renal Function

“…As CKD progresses, total phosphate excretion cannot keep pace with phosphate increasing. In turn, hyperphosphatemia induces an increase in serum FGF-23 level and promotes parathyroid hyperplasia (33,34). The extremely elevated FGF-23 possibly inhibits bone mineralization, and the secondary hyperparathyroidism may further aggravate hyperphosphatemia by bone resorption (35,36).…”

Parathyroid Cell Proliferation in Secondary Hyperparathyroidism of Chronic Kidney Disease

“…COX2 is expressed in parathyroid cells of normal, hyperplastic, and adenomatous parathyroid glands [ 102 ]. In parathyroids isolated from end-stage renal disease patients with advanced SHP, there was enhanced expression of both COX2 and PGE2 [ 103 ]. Increased COX2 expression was also reported in 5/6-nephrectomized rats fed a high-phosphorus diet, together with the increase in PTH levels, parathyroid size, and cell proliferation compared to controls.…”

Mechanism of calcitriol regulating parathyroid cells in secondary hyperparathyroidism

“…Multiple lines of evidence imply that cyclooxygenase 2(COX2), its metabolite prostaglandin E2 (PGE2) as well as its receptor EP2 enhance cell growth in SHPT patients with CKD ( Zhang et al, 2011 ; Zhang et al, 2019 ). This is a potential therapeutic target for secondary hyperparathyroidism.…”