Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease
Abstract
:1. Introduction
2. Atherosclerosis
3. Association between Osteocalcin and Atherosclerosis Outcomes
3.1. Measurement of Osteocalcin in Humans
3.2. In Vivo Osteocalcin Treatment and Cardiovascular Function in Animal Models
3.3. In Vivo Osteocalcin Treatment and Markers of Atherosclerosis Risk in Animal Models
4. Osteocalcin and Endothelial Function
4.1. In Vitro Osteocalcin Treatment in Human Cells
4.2. In Vitro Osteocalcin Treatment and Markers of Atherosclerosis Risk in Animal Cells
5. Osteocalcin and Vascular Calcification
5.1. Osteocalcin and Calcified Human Vascular Tissue
5.2. Vascular Calcification and Osteocalcin in Animal Models
6. The Putative Osteocalcin Receptor: GPRC6A
7. Future Directions
8. Summary and Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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First Author, Year [Ref.] | Experimental Overview | Measurement of Vascular Function | Results |
---|---|---|---|
Dou, 2014 [55] | ApoE-/- mice received ND or HFD and treatment daily for 12 weeks with vehicle or total osteocalcin (30 ng/g) | BP, heart rate, and isometric myography | In vivo: mean and diastolic BP normalized by osteocalcin treatment in HFD group, no change in systolic BP or heart rate. Ex vivo: 20% improvement in relaxation in osteocalcin-treated mice on HFD |
Huang, 2017 [56] | Sprague Dawley rats induced with diabetes via STZ injection and received ND or HFD, daily treatment of vehicle or total osteocalcin (30 ng/g) for 12 weeks | BP, PWV, heart rate, pulse pressure, and mean arterial pressure | PWV normalized in osteocalcin-treated rats with diabetes compared to diabetic rats treated with vehicle, no change in BP, heart rate, mean arterial pressure, and pulse pressure |
Kondo, 2016 [57] | Wild type C57BL/6 mice received HFD and treated 5 times a week for 10 weeks with vehicle or ucOC (30 ng/g) | Nitric oxide production | Increased nitric oxide concentration in ucOC-treated mice compared to vehicle-treated mice |
Zhou, 2013 [58] | C57BL/6J mice received ND or HFD for 8 weeks with daily injections of vehicle or ucOC (30 ng/g) | Autophagy and ER stress | Autophagy and ER stress attenuated in mice receiving ucOC |
First Author, Year [Ref.] | Experimental Overview | Outcomes | Results |
---|---|---|---|
Dou, 2014 [55] | HUVECs incubated with total osteocalcin (10–150 ng/mL) for 15 min–2 h. Descending aorta of ApoE-/- mice, previously treated with osteocalcin, incubated with LY294002 (10 µmol/L) and Akt inhibitor V (5 µmol/L) | eNOS, Akt, and PI3K phosphorylation and expression | Max phosphorylation of eNOS and Akt with 100 ng/mL of osteocalcin. Max phosphorylation of eNOS and Akt occurred after 1 h and 2 h, respectively. In aorta, PI3K, Akt, and eNOS phosphorylation and expression increased, inhibited with LY294002 and Akt inhibitor V |
Kondo, 2016 [57] | HAECs incubated with ucOC (5, 25, and 100 ng/mL) and cOC (25 and 100 ng/mL) for 30 min | eNOS phosphorylation | Incubation of ucOC increased eNOS phosphorylation in a dose-dependent manner, cOC had no effect |
Jung, 2013 [61] | HAECs incubated with ucOC (0.3–30 ng/mL), linoleic acid (100 µmol/L for 16 h), and wortmannin (100 nmol/L for 15 min) | Nitric oxide concentration, eNOS and Akt phosphorylation and apoptosis | UcOC increased eNOS and Akt phosphorylation and nitric oxide concentration, which was inhibited by wortmannin. UcOC attenuated linoleic acid-induced apoptosis |
Guo, 2017 [62] | HUVECs incubated with ucOC (5 ng/mL for 4 h), tunicamycin (5 µg/mL for 4 h), insulin (10 nM for 10 min), wortmannin, and Akti-1/2 (10 µM for 4 h) | Insulin resistance, ER stress | UcOC blocked ER stress and insulin resistance, which was inhibited by wortmannin and Akti-1/2 |
Zhou, 2013 [58] | Mouse VECs and VSMCs incubated with tunicamycin (5 µg/mL for 4 h), ucOC (5 ng/mL for 0, 2, 4, and 8 h), Akti-1/2 (10 µM for 4 h) and rapamycin (10 nM for 4 h) | Autophagy and ER stress | UcOC attenuated autophagy and ER stress in mouse VECs and VSMCs, which was inhibited by Akti-1/2 and rapamycin |
First Author, Year [Ref.] | Experimental Overview | Outcomes | Results |
---|---|---|---|
Levy, 1983 [69] | Human aortic and valve tissue | Osteocalcin and Gla levels | Osteocalcin and Gla levels higher in calcified tissue than in non-calcified tissue |
Levy, 1980 [70] | Human aortic and valve tissue | Gla levels | Higher Gla levels in calcified aorta and valves than non-calcified tissue |
Fleet, 1994 [71] | Human aortic tissue | Osteocalcin mRNA levels | Osteocalcin mRNA increased in calcified aorta and plaque compared to non-calcified aorta |
Tyson, 2003 [67] | Human aortic and carotid tissue | Osteocalcin expression | Calcified vessels had an increase in the expression of osteocalcin |
Severson, 1995 [72] | Cultured human aortic VSMCs | Immunostaining for osteocalcin | Minimal immunostaining of human VSMCs |
Proudfoot, 2002 [73] | Cultured human aortic VSMCs with lipid content modification | Osteocalcin expression | Osteocalcin expression increased in calcified cells compared to non-calcified cells, which was altered with the modification of lipid content |
Murshed, 2004 [74] | MGP-/- mice inter-crossed with pSM22α-Osteocalcin | Mineralization of aorta | Osteocalcin gain of function model did not inhibit the mineralization of mouse aorta |
Pal, 2010 [75] | OPG +/+ and OPG-/- mice | Calcification and mononuclear cells expressing osteocalcin | Increased calcification in OPG-/- mice, which was associated with an increased percentage of osteocalcin positive mononuclear cells |
Morony, 2008 [76] | Ldlr -/- mice fed HFD for 5 months and treated with OPG | Calcification, osteocalcin mRNA and circulating levels | Osteocalcin mRNA levels were unchanged, circulating osteocalcin increased over the 5 months, which was associated with calcification |
Akiyoshi, 2016 [77] | Thoracic aorta of C57BL/6 mice cultured to induced calcification | Osteocalcin expression | Osteocalcin expression increased in calcified thoracic aortas |
Idelevich, 2011 [78] | Cultured MOVAS cells induced with calcification and overexpressed with osteocalcin. Sprague Dawley rats induced with calcification | Mineralization, osteocalcin mRNA, metabolic signaling pathways | In vitro: overexpression of osteocalcin in MOVAS cells associated with mineralization and upregulation of insulin signaling In vitro: osteocalcin mRNA is increased in calcified vasculature and associated with activation of metabolic signaling pathways |
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Tacey, A.; Qaradakhi, T.; Brennan-Speranza, T.; Hayes, A.; Zulli, A.; Levinger, I. Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease. Nutrients 2018, 10, 1426. https://doi.org/10.3390/nu10101426
Tacey A, Qaradakhi T, Brennan-Speranza T, Hayes A, Zulli A, Levinger I. Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease. Nutrients. 2018; 10(10):1426. https://doi.org/10.3390/nu10101426
Chicago/Turabian StyleTacey, Alexander, Tawar Qaradakhi, Tara Brennan-Speranza, Alan Hayes, Anthony Zulli, and Itamar Levinger. 2018. "Potential Role for Osteocalcin in the Development of Atherosclerosis and Blood Vessel Disease" Nutrients 10, no. 10: 1426. https://doi.org/10.3390/nu10101426