Table 5.

Proposed regulators of VOC

Positive Regulators	Negative Regulators
Minerals: Ca++ Pi, Phosphate/Pit-1 → Cbfa-1	Fetuin-A
Vitamin D
BMP-2 Bone morphogenic protein	MGP Matrix gammacarboxyglutamate (Gla)-protein Inhibits BMP-2
Warfarin
Warfarin may also cause skin necrosis similar to CPLX via an impairment of Protein C with thrombosis in venules resulting in subcutaneous ischemia and Vitamin K – GLA inhibition.	GLA gammacarboxyglutamate
Inflammation: TNFalpha, IL-6	IL-10
Oxidized – retained – modified lipids (OxLDL-C, OxVLDL beta lipoproteins) and Low alpha lipoproteins: HDL-C	Osteopontin: OPN (may be a positive and negative regulator)
ROS Oxidative-Redox Stress	Osteoprotegerin OPG? Elevated in human atherosclerosis and CVD yet paradoxically when you have a mouse model with knockout of OPG there is increased osteoporosis and VOC.
A-FLIGHT TOXICITIES (table 3)
Glucose
Hormones: Insulin, IGF-1, Amylin, Leptin, and PTH
I or II Hyperparathyroidism
HYPOXIA activates hypoxia inducible factor Hif-1, ROS → Vascular angiogenesis Vasa Vasorum: Multipotential → Pericyte	RANK and RANKL These are involved but as with OPG the entire story is still evolving.
PERICYTE