Leptin induces osteoblast differentiation of human valvular interstitial cells via the Akt and ERK pathways.

Abstract

Calcific aortic valve disease (CAVD) affects 2-6% of the population over 65years, and age, gender, smoking, overweight, dyslipidemia, diabetes contribute to the development of this disease. CAVD results, in part, from the osteoblast differentiation of human valvular interstitial cells (VICs). This study aims to elucidate the effects of leptin on osteoblast phenotype of VICs and the signalling pathways involved. Patients who underwent aortic valve replacement for CAVD (n=43) were included in this study. Patients with coronary artery disease (CAD) without CAVD (n=129) were used as controls. Patients with CAVD had higher serum leptin concentrations than CAD patients (p=0.002). Leptin was found in calcific aortic valves, with higher concentrations in calcified versus non-calcified zones (p=0.01). Chronic leptin stimulation of human VICs enhanced alkaline phosphatase (ALP) activity and ALP, BMP-2 and RUNX2 expression and decreased osteopontin expression. Moreover, inhibiting Akt or ERK during leptin stimulation lowered the expression of osteoblast markers in VIC. Taken together, these findings indicate that leptin plays a critical role in CAVD development by promoting osteoblast differentiation of human aortic VICs in an Akt- and ERK-dependent manner. This study highlights the role of leptin in CAVD development, and further studies are needed to determine whether reducing circulating leptin levels or blocking leptin actions on VICs is efficient to slow CAVD progression.