Rare diseases caused by mutations within the BMP pathway – our research on PAH and FOP

Currently we are investigating the contribution of distinct BMP receptors in the regulation of vascular integrity and in particular in the endothelium. As we have shown BMPR2/Alk2 receptor complexes modulate endothelial adherence junctions by triggering VE-cadherin internalization via src-kinase (Benn et al., JCS, 2016). Furthermore BMP type I receptors Alk3 and Alk2 both play crucial and distinct roles in sprouting angiogenesis. Tip cells express Alk3 and induce the tip cell markers DLL4 and KDR via the BMP2-p38 pathway, while Alk2 is expressed in stalk cells to induce stalk-cell genes via the BMP6-Smad1/5 pathway (Benn et al., FASEB J, 2017).

This unique and balanced expression profile of different BMP receptors is crucial in maintaining vessel integrity and to cope with mechanical and inflammatory stimuli.

Mutations within the gene of BMPR2 have been described in the rare disease pulmonary arterial hypertension (PAH). PAH is characterized by narrowing of blood vessels within the lung, which results in increased blood preasure from the heart. As a consequence the vessels become stiffer and thicker. As BMP signaling is sensed by alterations in cellular mechanical forces, a vicious cycle accelerates the development of the disease locally. We are currently investigating the impact of BMP receptor mutations in endothelial cells in the context of sensing mechanical cues derived from the extracellular matrix. For this we developed biophysical and bioreactor systems to develop novel drug screening platforms.

Fibrodysplasia ossificans progressive (FOP) is a severely disabling genetic disorder in which bone forms at extraskeletal soft tissue sites. It is a rare autosomal dominant disorder occurring at a population frequency of about one in 2 million. The two main characteristic clinical features of classic FOP are congenital malformations of the great toes and progressive, episodic heterotopic ossification (HO), called flare-up, at distant sites. The mutation R206H in Alk2 is most prevalent found in FOP patients and causes a hypersensitive signal transduction. Bone precursor cells leading to these HO are amongst others derived from the endothelium through a process called Endothelial-to-Mesenchymal Transition (EndMT). As we found that Alk2 plays a crucial role in endothelial barrier function our current research focus is to investigate this in the context of FOP and other rare diseases.