Journal
JOURNAL OF VASCULAR RESEARCH
Volume 51, Issue 2, Pages 118-131Publisher
KARGER
DOI: 10.1159/000358920
Keywords
Osteoprotegerin; Receptor activator of NF-kappaB ligand; Interleukin 6; Smooth muscle cells; Vascular calcification; Osteochondrogenic differentiation
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Funding
- NIH [R01HL093469-01, R01DK094434-01]
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Objective: Vascular calcification is highly correlated with cardiovascular disease morbidity and mortality. Osteoprotegerin (OPG) is a secreted decoy receptor for receptor activator of NF-KB ligand (RANKL). Inactivation of OPG in apolipoprotein E-deficient (ApoE(-/-)) mice increases lesion size and calcification. The mechanism(s) by which OPG is atheroprotective and anticalcific have not been entirely determined. We investigated whether OPG-deficient vascular smooth muscle cells (VSMCs) are more susceptible to mineralization and whether RANKL mediates this process. Results: Lesion-free aortas from 12-week-old ApoE(-/-)OPG(-/-) mice had spotty calcification, an appearance of osteochondrogenic factors and a decrease of smooth muscle markers when compared to ApoE(-/-)OPG(+/+) aortas. In osteogenic conditions, VSMCs isolated from ApoE(-/-)OPG(-/-) (KO-VSMC) mice deposited more calcium than VSMCs isolated from ApoE(-/-)OPG(+/+) (WT-VSMC) mice. Gene expression and biochemical analysis indicated accelerated osteochondrogenic differentiation. Ablation of RANKL signaling in KO-VSMCs rescued the accelerated calcification. While WT-VSMCs did not respond to RANKL treatment, KO-VSMCs responded with enhanced calcification and the upregulation of osteochondrogenic genes. RANKL strongly induced interleukin 6 (IL-6), which partially mediated RANKL-dependent calcification and gene expression in KO-VSMCs. Conclusions: OPG inhibits vascular calcification by regulating the procalcific effects of RANKL on VSMCs and is thus a possible target for therapeutic intervention. (C) 2014 S. Karger AG, Basel
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