Sclerostin: moving from bone to lung

Introduction:

Pulmonary arterial hypertension (PAH) is characterized by increase pulmonary pressure and vascular remodelling as a consequence of smooth muscle cells proliferation and endothelial cells dysfunction. Dysregulation on WNT and BMP signalling and their crosstalk promotes PAH and disease progression. Hence, we hypothesize that sclerostin, a molecule regulating both WNT and BMP pathways, affects physiological homeostasis of the vasculature and contributes to the pathophysiology of PAH.

Material and methods:

Laser microdissected vessels from donor and PAH patients were used for microarray and pathway analysis. Expression analysis was performed in human isolated pulmonary arteries (PA) from PAH patients and from lung homogenate of animal models. Sclerostin stimulation (100 ng/ml) was performed on both endothelial (hPAEC, Lonza) and smooth muscle cells (hPASMC, isolated from human donor lungs). Proliferation was analyzed by thymidine incorporation.

Results:

Microarray analysis revealed sclerostin as the most upregulated gene in PA of PAH patients in comparison to donor, further confirmed by qPCR. Pathway analysis (KEGG) showed several dysregulated genes in WNT (e.g. RhoA, Axin) and BMP/TGFβ (e.g. SMAD7, NOGGIN) pathways in PA from PAH patients. Importantly, increased sclerostin was also observed in lungs from monocrotaline treated rats and hypoxia exposed mice where sclerostin localized in the vasculature. In vitro studies showed that sclerostin activates WNT dependent signaling involved in cell migration, cell-cell contact and proliferation in hPAEC but not in hPASMC.

Discussion:

These preliminary results suggest a potential role of sclerostin in modulating function and homeostasis of hPAEC in PAH, however the underlying mechanism needs further investigation.

Key words:

Pulmonary arterial hypertension, slcerostin, endothelial cells