Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice

Cardiovascular calcification is a common consequence of diabetes. High fat diets induce diabetes and arterial calcification in male low density lipoprotein receptor (LDLR) -/- mice; calcification occurs via Msx2 signaling that promotes the osteogenic differentiation of arterial myofibroblasts. We studied regulation of arterial osteogenesis by human parathyroid hormone (PTH) ( 1 - 34) ( also called teriparatide) in LDLR-/- mice fed diabetogenic diets for 4 weeks. LDLR-/- mice were treated with vehicle or 0.4 mg/kg of PTH( 1 - 34) subcutaneously five times/week. Gene expression was determined from single aortas and hind limb RNA by fluorescence reverse transcription-PCR. Valve calcification was determined by histological staining of cardiac sections using image analysis to quantify valve leaflet mineralization. PTH( 1 - 34) increased bone mineral content ( by dual energy x-ray absorptiometry) in LDLR -/- mice, with induction of osseous osteopontin (OPN) expression and serum OPN levels (> 150 nM); PTH( 1 - 34) did not significantly change serum glucose, lipids, body weight, or fat mass. PTH( 1 - 34) suppressed aortic OPN and Msx2 expression > 50% and decreased cardiac valve calcification 80% (8.3 +/- 1.5% versus 1.4 +/- 0.5%; p < 0.001). Of the known circulating regulators of vascular calcification ( OPN, osteoprotegerin, and leptin), PTH( 1 - 34) regulated only serum OPN. We therefore studied actions of PTH( 1 - 34) and OPN in vitro on cells induced to mineralize with Msx2. OPN ( 5 - 50 nM) reversed Msx2-induced mineralization. PTH( 1 - 34) inhibited mineralization by 40% and down-regulated Msx2 in aortic myofibroblasts. PTH( 1 - 34) inhibits vascular calcification and aortic osteogenic differentiation via direct actions and potentially via circulating OPN. PTH( 1 - 34) exerts beneficial actions at early stages of macrovascular disease responses to diabetes and dyslipidemia.