Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice
| Autor: | Jian Su Shao, Nichole Charlton-Kachigian, Su Li Cheng, Dwight A. Towler, Arleen P. Loewy |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Male
medicine.medical_specialty Sialoglycoproteins Down-Regulation Gene Expression Hyperlipidemias Biochemistry Models Biological Mice stomatognathic system Osteoprotegerin Cardiovascular calcification Osteogenesis Internal medicine Teriparatide medicine Cardiac valve calcification Diabetes Mellitus Animals Osteopontin Molecular Biology Aorta Calcium metabolism Homeodomain Proteins biology Chemistry Reverse Transcriptase Polymerase Chain Reaction Spectrometry X-Ray Emission Cell Differentiation Cell Biology Fibroblasts medicine.disease Up-Regulation DNA-Binding Proteins Arterial calcification Endocrinology Receptors LDL LDL receptor biology.protein RNA Calcium Calcification Signal Transduction |
| Zdroj: | The Journal of biological chemistry. 278(50) |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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