Teriparatide (Human Parathyroid Hormone (1–34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice

Abstract

Over a century ago, the pathologist Rudolph Virchow recognized the involvement of calcified tissues in the pathobiology of vascular diseases (1). Coining the term "endarteritis deformans" he descriptively denoted the histological character of the atherosclerotic plaque as exhibiting features of a progressively calcified scar tissue that forms in response to a vascular inflammatory state. Since then, a minimum of three histoanatomic variants of macrovascular calcification, atherosclerosis, calcific valvular sclerosis, and medial artery calcification, have been shown arise in response to metabolic, mechanical, infectious, or inflammatory diseases (2-4). Both early and recent studies point to cellular processes that resemble bone formation at the histological level. However, Demer and co-workers (5) were the first to provide direct evidence for active osteogenic regulation of vascular calcification. They identified BMP2, 1 a powerful bone morphogenetic protein, as a key component of the mineralized atherosclerotic plaque (5). Thus, rather than being a passive process, vascular calcification is in part subject to active regulation. Once thought benign, the deleterious clinical consequences of calcific vasculopathy are now becoming clearer (6 -10). Patients with diabetes have increased mortality and 3-fold increased risk for lower extremity amputation in the setting of medial artery calcification (11). In patients with asymptomatic aortic stenosis, a moderate to severe echocardiographic valve calcification score is the single best predictor of vascular disease progression, again exceeding blood pressure control, lipid control, and diabetes control in positive predictive value (12). Risk for stroke, particularly notable in post-menopausal women, is increased in the presence of aortic arch calcification (13). Multiple metabolic stimuli contribute to calcific vascular disease initiation and progression in patients with diabetes, hypercholesterolemia, poor glycemic control, and phosphate retention associated with renal failure contributing to vascular calcium accumulation (2). A fundamental understanding the molecular physiology of vascular calcification will provide insights useful for developing strategies to prevent and treat this macrovascular disease process.Metabolic contributions to vascular calcification are well known and include hypercholesterolemia, diabetes, hyperphosphatemia, vitamin D toxicosis, magnesium deficiency, and chronic renal insufficiency (2). The mechanisms whereby the metabolic insults of diabetes initiate and propagate vascular calcification are beginning to be examined in detail. Hyperglycemia, hyperlipidemia, and oxidative stress (3, 14) up-regulate the expression of vascular signaling molecules that promote mineral deposition in a process that resembles craniofacial bone formation (15). Hyperglycemia and hyperlipidemia have

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

“…Clinically, patients with CKD suffer from high cardiovascular mortality and adverse cardiovascular events, including coronary microvascular dysfunction, subclinical aortic valve calcification, increased aortic stiffness, endothelial dysfunction and hypertension (37,38). Furthermore, PTH reduces VC mediated by the BMP2-Msh Homeobox 2-Wnt signaling pathway (39)(40)(41).…”

BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction

“…Similar to the phenotype of PTHrP -/-mice, mammary buds are reported to form in MSX2 -/-mice, but their development arrests at E16.5 and no ductal outgrowth is formed (Satokata et al, 2000). Interestingly, activation of the PTH1R modulates Msx2 gene expression in aortic adventitial cells and in osteoblasts (Shao et al, 2003;Shao et al, 2005;Bidder et al, 1998;Dodig et al, 1999;Towler et al, 2006). In this study, we examined potential interactions between PTHrP and BMP signaling during early embryonic mammary gland development.…”

MINT, the Msx2 Interacting Nuclear Matrix Target, Enhances Runx2-dependent Activation of the Osteocalcin Fibroblast Growth Factor Response Element

“…The next day, MC3T3E1 cells were switched to osteogenic differentiation media (10% fetal calf serum in ␣-minimal essential medium, supplemented with 50 g/ml ascorbic acid and 10 mM ␤-glycerol phosphate) and cultured for an additional 10 days. RNA was subsequently extracted, contaminating DNA was removed with DNaseI, and OC, OPN, and ␤-tubulin mRNA accumulation expression evaluated by fluorescent RT-PCR as described previously (18,28). The experiment was repeated twice.…”