Characterization of the liver phenotype of the BMP-9 knock-out mouse

Bone morphogenetic protein 9 (BMP-9) is a hepatic cytokine that belongs to the transforming growth factor beta superfamily. We previously showed that high levels of BMP-9 in the liver counteract regenerative processes and promote hepatic fibrogenesis. Nevertheless basal levels of BMP-9 are always present and circulate with the blood stream in an active confirmation, suggesting that there might be relevant physiological functions of this cytokine. The general BMP-9 knock-out mouse does not present with any obvious phenotype. The mice are vital and fertile. However, a detailed characterization of these mice has not been performed yet which prompted us to investigate this with focussing on any possible changes mainly in the liver.

6 C57BL/6 wild-type and 6 C57BL/6 knock-out mice (all male) were killed at the age of 3 – 6 months. Blood and livers of all mice were asserved and body and liver weights were determined.

When analyzing the serum samples from the knock out animals we found that general liver parameters like ALT, LDH and Triglycerides were reduced whereas Cholinesterase, AP and Glucose were increased. AST and Cholesterol were unchanged. While overall the mice appeared rather over-weight with partially massive fat deposition around the organs, the livers appeared quite normal and were rather small. This resulted in a significantly decreased liver to body weight ratio in the KO mice. On the RNA level we analyzed the expression of typical BMP-target genes like Id1 and hepcidin in total liver lysates. Unexpectedly both genes were not reduced, in contrast they showed a tendency of increase which slightly missed significance levels (more samples per mouse will be analyzed soon). In an attempt to explain this finding by a possible upregulation of other BMP's we checked for BMP-2 and -6 and indeed both were slightly upregulated. Another unexpected finding was that although blood glucose levels were enhanced, the glucose-import protein Glut2 was very significantly upregulated in the KO livers.

In summary these data already show that there are indeed systemical effects of BMP-9 which seem to affect hepatic glucose and fat metabolism. Further investigations are needed to understand these complex mechanisms of BMP-9 actions in the liver and the whole body.