Teriparatide (human parathyroid hormone (1-34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice.
Open accessAbstract
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.
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An LDL receptor knockout mouse on a high-fat diet recapitulates progressive atherosclerosis and vascular calcification with elevated endogenous OPG.
“Those very conditions were recently described in an animal model involving LDL receptor knockout mice on a high-fat diet (167).”
From Receptor Activator of Nuclear Factor κB Ligand and Osteoprotegerin Regulation of Bone Remodeling in Health and Disease (2008) · cites this paper as [167]
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Self-citation
- Authors
- Shao, J.-S., Cheng, S.-L., Charlton-Kachigian, N., Loewy, A. P., & Towler, D. A.
- Affiliations
- Barnes-Jewish Hospital (US)
- Corresponding author
- Towler, Dwight A.
- ORCID
- Towler, Dwight A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 278
- Issue
- 50
- Pages
- 50195-50202
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1974287326
- Cited by
- 174
- References
- 55
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 3 · 2015: 5 · 2014: 12 · 2013: 7 · 2012: 8
- FWCI
- 7.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-69229, R01HL069229)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- teriparatide, human parathyroid hormone (1-34), vascular calcification, osteogenic differentiation, Msx2, osteopontin, Ldlr-deficient mice, diabetes mellitus, valve calcification, bone mineral content, dyslipidemia, macroangiopathy
- MeSH terms
- Animals, Aorta, Calcium, Cell Differentiation, Diabetes Mellitus, DNA-Binding Proteins, Fibroblasts, Hyperlipidemias, Male, Models, Biological, Osteogenesis, Receptors, LDL, RNA, Sialoglycoproteins, Spectrometry, X-Ray Emission, Signal Transduction, Down-Regulation, Up-Regulation, Gene Expression, Homeodomain Proteins, Teriparatide, Reverse Transcriptase Polymerase Chain Reaction, Mice, Osteopontin
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