Role of sclerostin in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vasoconstriction and vascular remodelling of the pulmonary arteries leading to vascular obstruction and ultimately to right heart failure. Numerous pathomechanisms have been investigated in order to elucidate the origin of the disease, but the aetiology of PAH remains unclear. Many "bone-like" proteins such as osteopontin and BMPRII have already been studied in PAH. Especially mutations in the BMPRII gene, which impaired the BMP signaling were identified as the cause for the familial form of the PAH. In addition WNT signalling, involved in bone homeostasis as well, is also known to be altered in PAH. Recently, sclerostin has been shown to inhibit BMP signalling and alter WNT signalling homeostasis. We suggest here a crucial role of sclerostin in modulating BMP and WNT downstream signalling and their crosstalk, resulting in alteration of normal vasculature physiology. Our preliminary results show that sclerostin is highly expressed in pulmonary arteries of PAH patients compared to donors and in animal model of pulmonary hypertension. We also observed an influence of sclerostin on WNT pathways which are involved in migration and barrier integrity of endothelial cells. In this study we aim to investigate the influence of sclerostin on WNT and BMP signalling, their crosstalk and the consequent effect on endothelial cells. This approach will increase the understanding of the molecular mechanisms underlying vascular remodeling and highlight sclerostin as a new important player. In addition, a possible new therapeutic approach could be identified for the treatment of PAH which is an important medical need.