Two Signaling Pathways Implicated in SSc-PAH

Clinicians, scientists, and researchers have acknowledged an association between systemic sclerosis (SSc) and pulmonary arterial hypertension, and have even created the disease category “SSc-PAH,” or SSc-related PAH. This category of PAH is remarkably similar to heritable PAH, yet the basis for the similarity has remained unknown.

In an effort to shed more light on the relationship, a research group from University College London recently worked on transforming growth factor beta (TGFβ) signaling to determine if there is any relation between SSc and PAH. The group had previously determined that a mouse model of SSc generated via TGFβ genetic alterations leads to the development of PAH when exposed to pulmonary endothelial cell injury. Accordingly, the group used this mouse model to investigate signaling pathways in the lungs and found implications of bone morphogenetic protein (BMP) signaling in SSc-PAH.

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As described in “Increased Degradation of BMPR2 in a TGFβ Dependent Transgenic Mouse Model of Scleroderma with Susceptibility to Pulmonary Arterial Hypertension,” presented by Dr. Adrian J. Gilbane at the 2014 American College of Rheumatology Meeting in November, the genetically altered mice developed structural pulmonary vasculopathy. This led to elevated right ventricular pressures because smooth muscle cells surrounding blood vessels hypertrophied and narrowed the blood vessels, a hallmark of PAH.

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By isolating lung tissue and culturing fibroblasts from the tissue, the researchers identified an increased level of TGFβ signaling as a result of increased levels of pSmad2/3, transcription factors that lead to DNA transcription. Additionally, BMP receptor 2 protein (BMPRII) was significantly reduced in the mice. This result was clinically relevant, as tissue from SSc patients also showed reduced BMPRII and increased DNA transcription for BMPRII.

Applying a proteasome inhibitor known as MG132 restored BMPRII protein levels to SSc fibroblasts, which returned a normal level of BMP signaling, despite the initial increase in TGFβ signaling. “Here we demonstrate the TβRIIΔk-fib transgenic murine model of PAH-SSc exhibits reduced expression of BMPRII as a reciprocal response to increased TGFβ signaling,” stated the researchers. “Collectively our data suggests loss of BMPRII expression by non-genetic means may contribute to the development of PAH in SSc.”