Bone morphogenetic protein 6 and oxidized low-density lipoprotein synergistically recruit osteogenic differentiation
Lai-Ming Yung1, Gonzalo Sánchez-Duffhues2, Peter Ten Dijke2
1Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, USA.
Insights
Bone morphogenetic protein 6 (BMP6) and oxidized low-density lipoprotein (oxLDL) promote vascular calcification by inducing osteogenic differentiation in endothelial cells (ECs). This process involves oxidative stress and BMP signaling, contributing to atherosclerosis.
Area of Science:
- Vascular Biology
- Cellular Differentiation
- Biochemistry
Background:
- Vascular calcification is a significant contributor to mortality in atherosclerosis, chronic kidney disease, and diabetes.
- Vascular lesions contain cells resembling osteoblasts and chondroblasts, suggesting ossification processes driven by vascular cell plasticity.
- Bone morphogenetic protein (BMP) signaling exacerbates atherosclerotic calcification, while its inhibition reduces vascular inflammation and calcification in mice.
Purpose of the Study:
- To investigate the hypothesis that endothelial cells (ECs) undergo osteogenic differentiation in response to BMP signaling and pro-atherogenic stimuli.
- To elucidate the mechanisms by which BMPs and oxidized low-density lipoprotein (oxLDL) induce vascular calcification.
Main Methods:
- Bovine aortic endothelial cells (BAECs) and human aortic endothelial cells were treated with various BMP ligands, oxLDL, and hydrogen peroxide (H2O2).
- Gene expression analysis focused on osteogenic and chondrogenic transcription factors (Runx2, Msx2, Osterix, Osteopontin).
- Mineralization assays were performed, with interventions including reactive oxygen species scavengers and BMP type I receptor kinase inhibitors.
Main Results:
- BMP6 and BMP9 showed potent signaling in BAECs, with BMP6 inducing osteogenic differentiation.
- BMP6 and oxLDL synergistically induced osteogenic differentiation and mineralization in ECs, consistent with endothelial-to-mesenchymal transition.
- H2O2 was essential for oxLDL-induced gene regulation, and BMP6/oxLDL treatments upregulated specific osteogenic markers, effects blocked by ROS scavenging or kinase inhibition.
Conclusions:
- Findings suggest a mechanism linking BMP signaling, oxidative stress, and inflammation in vascular calcification associated with atherosclerosis.
- Endothelial cells can differentiate into osteogenic phenotypes under specific stimuli, contributing to vascular calcification.
- BMP6 and oxLDL act synergistically to promote EC osteogenic differentiation and mineralization, highlighting potential therapeutic targets.
Aims:
Vascular calcification contributes to mortality and morbidity in atherosclerosis, chronic kidney disease, and diabetes. Vascular calcific lesions contain osteoblast- and chondroblast-like cells, suggesting a process of endochondral or membranous ossification thought to result from the phenotypic plasticity of vascular cells. Bone morphogenetic protein (BMP) signalling potentiates atherosclerotic calcification, whereas BMP inhibition attenuates vascular inflammation and calcification in atherogenic mice. We hypothesized endothelial cells (ECs) may undergo osteogenic differentiation in response to BMP signalling and pro-atherogenic stimuli.
Methods And Results:
Among various BMP ligands tested, BMP6 and BMP9 elicited the most potent signalling in bovine aortic endothelial cells (BAEC), however, only BMP6 induced osteogenic differentiation. BMP6 and oxidized low-density lipoprotein (oxLDL) independently and synergistically induced osteogenic differentiation and mineralization, in a manner consistent with endothelial-to-mesenchymal transition. Treatment of ECs with BMP6 or oxLDL individually induced osteogenic and chondrogenic transcription factors Runx2 and Msx2, whereas treatment with BMP6 and oxLDL synergistically up-regulated Osterix and Osteopontin. Production of H2O2 was necessary for oxLDL-induced regulation of Runx2, Msx2, and Osterix in BAEC, and H2O2 was sufficient by itself to up-regulate these genes. Mineralization of ECs in response to BMP6 or oxLDL was abrogated by scavenging reactive oxygen species or inhibiting BMP type I receptor kinases. Similar synergistic effects of BMP and oxLDL upon osteogenic and chondrogenic transcription and phenotypic plasticity in human aortic endothelial cells were observed.
Conclusion:
These findings provide a potential mechanism for the observed interactions of BMP signalling, oxidative stress, and inflammation in recruiting vascular calcification associated with atherosclerosis.
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