Bone morphogenetic proteins (BMP-2 to BMP-15) belong to the Transforming Growth Factor (TGF)-β superfamily and, besides their well-documented roles during embryogenesis and bone formation, some of them have recently been described to be involved in the pathogenesis of different organs, including the liver. The role of BMPs in liver damage responses including hepatocellular carcinoma (HCC) development has only begun to be addressed and strong evidence supports the concept of a pro-tumorigenic role of BMP signaling in HCC cells. BMP-9 (also termed Growth and Differentiation Factor (GDF)-2) represents the most recently discovered member of the BMP family. We have previously demonstrated that in HCC patient samples BMP-9 expression was positively associated with the tumor seize (“T stage”) and that it enhanced cell migration and induced epithelial to mesenchymal transition (EMT) in HCC cells in vitro. In another study we recently found that BMP-9 promotes growth in HCC cells, but not in non-transformed hepatocytes. Published as well as unpublished results obtained with primary hepatocytes support the concept of a dual function of BMP-9 in the liver: while in primary, non-malignant cells BMP-9 stabilizes the epithelial phenotype and inhibits proliferation, in HCC cells it induces cell growth and the acquisition of a migratory phenotype. In this review article we summarize current knowledge about BMPs in liver diseases, with special focus on the role of BMP-9 in HCC development and progression, that may provide new clues for a better understanding of the contribution of BMP-signaling to chronic liver diseases.

Bone morphogenetic proteins (BMPs) belong to the TGF-β superfamily and were first discovered as potent bone homeostasis regulators for their ability to induce endochondral bone formation, ectopic bone formation and fracture repair. A preeminent role of BMP signaling in developmental control of cell type specification, differentiation and organogenesis is also well established. More recently, a role for BMPs in adult tissue homeostasis has started being revealed. Thus, new studies show that BMPs regulate many cellular processes such as proliferation, apoptosis, differentiation and migration in many tissues and organs. As a consequence, dysregulation of BMP activity can have pathological consequences, and there is mounting evidence for the involvement of BMPs in different human diseases. In this review, we have focused on summarizing the present knowledge on the relevance of BMPs in liver physiology and pathophysiology, from the well-recognized role in liver development to the emerging contribution to the function and dysfunction of the adult liver. While no doubts seem to rise about the regulatory activities of BMPs on metabolic pathways in the liver, potential pro- and anti-fibrogenic and tumorigenic actions will likely be a matter of debate during coming years. Collectively, the work here presented provides the basis to consider BMPs as potential targets of intervention in liver diseases.