Arterial osteoprotegerin:: increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-α

Aims/hypothesis: Extracellular matrix modifications and linear medial calcifications are elements of diabetic macroangiopathy. We hypothesised that the bone-related protein osteoprotegerin (OPG) may occur in altered amounts in the arterial wall in diabetes, putatively associated with altered synthesis from vascular cells. Methods: The amount of OPG in the thoracic aorta, obtained at autopsy from 21 diabetic and 42 sex- and age-matched controls, was measured in tissue extracts by an ELISA. The production of OPG was estimated in conditioned media by an ELISA, and OPG mRNA was estimated by RT-PCR in vascular cells grown in vitro. Results: The content of OPG was increased in tunica media samples from diabetic individuals. No differences between diabetic and non-diabetic subjects were observed in tunica intima. Human vascular smooth muscle cells (HVSMCs) produced approximately 30 times more OPG than human umbilical vein endothelial cells. The OPG production into the medium decreased dose- and time-dependently after insulin treatment (maximal effect similar to 60% of control) in HVSMCs, whereas TNF-alpha supplement gave rise to increased OPG synthesis in a time- and dose-dependent manner (maximal effect similar to 200% of control). Similar effects on OPG mRNA expression were observed. Addition of growth hormone (10 ng/ml) or extra glucose (25 mmol/l) to the growth medium had no effect. Conclusions/interpretation: Increased OPG concentrations in the arterial wall in diabetes may be part of generalised matrix alterations, putatively related to the development of vascular calcifications. Altered arterial OPG content may be a consequence of the effects of hormones and cytokines, like insulin and TNF-alpha.