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Project AP

Role of bone morphogenetic protein (BMP)-9
in the liver

Bone morphogenetic proteins (BMPs) belong to the TGF-beta family of cytokines with BMP-9 and the closely related BMP-10 being the most recently discovered members. Whereas BMP-10 seems to be mainly expressed in the heart, BMP-9 is constitutively produced by the liver and is secreted to the blood stream in an active conformation.
Effects of BMP-9, e.g. in bone, have been studied quite intensively already, but regarding its potential role in the liver there is still a lot to be explored in detail. Data that we previously published showed that high levels of BMP-9 lead to enhanced liver damage, especially liver fibrosis in vivo. We additionally identified the hepatic stellate cells (HSC) as hepatic source for BMP-9 and could further show that the high affinity BMP-9 receptor, ALK-1, is mainly expressed in liver sinusoidal endothelial cells (LSEC) and Kupffer cells (KC) but rather not in HSC and hepatocytes. Other results point to a BMP-9 mediated enhanced inflammatory acute phase response (APR) in hepatocytes. Interestingly the bacterial toxin lipopolysaccharide (LPS) seems to directly counter-act BMP-9 effects in the liver, whereas BMP-9 expression is induced by IL-6 (in vitro).
We aim at investigating the underlying molecular mechanisms of these BMP-9 effects including the cross-talk between liver and gut. 
In order to best translate the obtained results to the human in vivo situation we use not only animal models (mice) but also 2D and 3D cultures of primary human liver or gut cells. This way, we focus on the characterization of the BMP-9 mediated interactions between the different liver cell types: how do LSEC and KC respond to BMP-9? Do BMP-9 mediated effects on these cells lead to a pro-fibrogenic feed-back on HSC and on the APR of hepatocytes? How do BMP-9 KO or macrophage-specific Alk1 KO mouse livers regenerate upon acute intoxication with LPS?
Finally, we collected blood and tissue samples from patients with increasing stages of fatty liver disease (with or without diabetes) and measured the levels of BMP-9, LPS and the liver-protective cytokines FGF19 and FGF21. Unexpectedly, we found that there is substantial BMP-9 expression also in the small intestine and current data point to a significant correlation between intestinal BMP-9 expression and diabetes manifestation in the patients. 
Our final goal is to find out whether targeting BMP-9 might indeed have potential as new therapy approach to support a healthy liver in vivo, in patients at risk of developing fatty liver disease, cirrhosis and finally liver cancer.

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