Role of bone morphogenetic protein (BMP)-9

in the liver

Katja Breitkopf-Heinlein

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 not much is known up to now. Data that we recently published in Gut show 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.

We aim at investigating the underlying molecular mechanisms of these BMP-9 effects and cross-talks. We did not observe any direct HSC activating properties of BMP-9 in vitro implying that its pro-fibrogenic effects in vivo might be of rather indirect nature. We plan to test the hypothesis that HSC activation in vivo is the result of BMP-9 mediated cross-talk between different non-parenchymal liver cell types, especially between LSEC, KC and HSC leading to enhanced fibrogenesis and APR in hepatocytes.  Thereby signals from the LSEC should control consequent liver damage.

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 cells. In 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 mouse livers regenerate upon acute intoxication with LPS?

Finally we are collecting blood samples from liver patients and will measure the BMP-9 and LPS levels. Is there any significant correlation between the kind of liver damage or the stage of the disease with BMP-9 levels in serum of patients? Can BMP-9 perhaps even serve as new serum marker for liver damage?

After having uncovered the molecular mechanisms of BMP-9 effects in the liver our final goal is to test whether targeting BMP-9 might indeed have potential as new therapy approach to support liver regeneration in patients.