Parathyroid hormone promotes osteoblastic differentiation of endothelial cells via the extracellular signal‑regulated protein kinase 1/2 and nuclear factor‑κB signaling pathways

Abstract

Abstract. Vascular calcification (VC) occurs in patients with chronic kidney disease (CKD) and contributes to cardiovascular dysfunction and mortality. Parathyroid hormone (PTH) is a crucial regulator of VC. High PTH serum levels constitute as a major risk factor for patients with CKD. However, the effect and mechanism of PTH on osteoblastic differentiation in endothelial cells have not been fully elucidated. In the present study, the role of PTH in VC was investigated using an in vitro calcification model. Endothelial cells were stimulated with PTH in the femto-to picomolar range. As determined by western blot analysis and ELISA, osteoblastic differentiation, as indicated by the BMP2 marker, occurred with maximum effect at 1x10 -10 mmol/l PTH. The results indicate that PTH promotes osteoblastic differentiation of endothelial cells, as demonstrated by the increased expression of bone morphogenetic protein (BMP) 2 and BMP4. In addition, western blot analysis revealed that PTH activated the extracellular signal-regulated protein kinase (Erk)1/2 and nuclear factor (NF)-κB signaling pathways. However, reverse transcription-quantitative polymerase chain reaction demonstrated that inhibitors specific to Erk1/2 and NF-κB eradicated the effect of PTH treatment on BMP2, BMP4, ALP and RUNX2 expression. These results demonstrate that PTH promotes the osteoblastic differentiation of endothelial cells via the Erk1/2 and NF-κB signaling pathways, which suggests a potential role of PTH in the promotion of VC. These findings provide an insight into the association between PTH and cardiovascular disease.

Atherosclerosis in SLE: a potential role for serum parathormone levels

“…[33][34][35] In addition, PTH has been found to influence the expression of proinflammatory endothelial factors, such as the receptor of advanced glycation end products and interleukin 6 36 and to promote osteoblastic differentiation of endothelial cells through induction of bone morphogenetic proteins. 37 Towards the same direction, arterial wall thickening, 33 endothelial dysfunction, 38 number of stenotic coronary arteries 14 and increase in CVD mortality 15 have been reported in association with high PTH levels. In the current There is ample evidence of 25-OHD involvement in CVD development, 6-8 40 and 25-OHD deficiency has been shown to influence endothelial dysfunction in both animal models 41 and patients with SLE, 42 possibly as a result of increase in interferon activity, 41 43 previously shown to be involved in SLE-related atherosclerosis.…”

“… 33–35 In addition, PTH has been found to influence the expression of proinflammatory endothelial factors, such as the receptor of advanced glycation end products and interleukin 6 36 and to promote osteoblastic differentiation of endothelial cells through induction of bone morphogenetic proteins. 37 Towards the same direction, arterial wall thickening, 33 endothelial dysfunction, 38 number of stenotic coronary arteries 14 and increase in CVD mortality 15 have been reported in association with high PTH levels. In the current study, none of the patients with heightened PTH levels had evidence of primary hyperparathyroidism; advanced age and reduced 25-OHD serum levels seemed to account for these cases.…”

Evaluation of global and regional left ventricular myocardial work by echocardiography in patients with chronic kidney disease

“…Changes in left ventricular morphology and structure mainly manifested as left ventricular hypertrophy (LVH), which may be caused by increased preload and afterload, anemia, proteinuria, and bone‐mineral metabolism disorders 10 . In CKD patients, Stiffness of the peripheral vascular wall and heart valve and vascular calcification, which are caused by secondary hyperparathyroidism and calcium and phosphorus metabolism disorders, result in increased pulse pressure and cardiac pressure load 11,12 . In addition, renal ischemia activates the renin–angiotensin–aldosterone system, resulting in arteriole constriction and water–sodium retention 13 .…”

Anabolic Therapies in Osteoporosis and Bone Regeneration

“…Mechanistically, transactivation of Runx2, the transcription factor crucial for osteoblast differentiation, is activated by PTH through cAMP/protein kinase A [28]. Moreover, ERK1/2-mitogen-activated protein kinase and phosphatidylinositol phosphate signalling pathways are also activated by PTH, which results in an enhanced osteoblast proliferation [29].…”