Potential Roles of Bone Morphogenetic Protein (BMP)-9 in Human Liver Diseases

Abstract

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 Published as well as unpublished results obtained with primary hepatocytes support the concept of a dual function of BMP-9 in the liver: while in primary, non-malignant cells BMP-9 stabilizes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.

BMP-9 interferes with liver regeneration and promotes liver fibrosis

“…Although BMP-9 is constitutively expressed in healthy liver,17 19 knowledge about its physiological functions is still very limited (for review, see45). Whereas inhibition of BMP-9/ALK1 signalling is already discussed as a potential anti-angiogenic strategy in cancer46 and clinical application of rhBMP-9 was recently presented as a potentially promising new approach to promote fracture healing,47 its possible roles during acute or chronic liver damage were only insufficiently investigated up to now.…”

All-trans retinoic acid restored the osteogenic ability of BMP9 in osteosarcoma through the p38 MAPK pathway

“…BMP9 was first identified in the developing mouse liver as playing an important role in regulating iron metabolism and the development of cholinergic neurons (39). BMP9 has been implied in tumourigenesis (7)(8)(9)(10)(11)(12)(13)16,(19)(20)(21)(22).…”

Functional Expression of P-glycoprotein and Organic Anion Transporting Polypeptides at the Blood-Brain Barrier: Understanding Transport Mechanisms for Improved CNS Drug Delivery?

“…Members of the TGF-β superfamily of signaling ligands, which include BMPs, activins, and TGF-βs, bind to two types of transmembrane serine-threonine kinase receptors known as type I and type II receptors (62,63). BMPs comprise the largest group of ligands within the TGF-β family (64) and play an essential role in cellular processes including differentiation, proliferation, angiogenesis, apoptosis, and bone formation (65,66). In mammals, seven BMP type I receptors, (i.e., ALK 1–7), and three BMP type II receptors (i.e., BMPR-II, ActR-II and ActR-IIB) have been identified (62).…”

“…Awell-characterized agonist for ALK1 is bone morphogenetic protein (BMP)-9, which plays a role in several cellular processes including differentiation, proliferation, angiogenesis, and bone formation (65,66,87). BMP-9 is primarily produced by the liver and is present in the systemic circulation at a concentration of 5 ng/mL, which is above its EC 50 (66) and has been shown to physiologically induce constitutive Smad1/5/8 phosphorylation in endothelial cells (88). In another study using human dermal microvascular endothelial cells, Smad1/5/8 activation was demonstrated in a dose-dependent manner with BMP-9.…”