BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration

Abstract

Bone Morphogenetic Proteins (BMPs) belong to the Transforming Growth Factor-β (TGF-β) family. Initially identified due to their ability to induce bone formation, they are now known to have multiple functions in a variety of tissues, being critical not only during development for tissue morphogenesis and organogenesis but also during adult tissue homeostasis. This review focus on the liver as a target tissue for BMPs actions, devoting most efforts to summarize our knowledge on their recently recognized and/or emerging roles on regulation of the liver regenerative response to various insults, either acute or chronic and their effects on development and progression of liver fibrosis in different pathological conditions. In an attempt to provide the basis for guiding research efforts in this field both the more solid and more controversial areas of research were highlighted.

Keywords: BMP; TGF-β; chronic liver disease; fibrosis; liver; regeneration.

Figure 1

BMP-triggered signalling pathway and major regulators. BMP ligand binds to its membrane serine/threonine kinase receptors type I and type II. Once the heterotetrameric complex is formed, constitutively active type II receptor transphosphorylates the type I receptor to initiate intracellular signalling. In the canonical pathway, R-Smads are phosphorylated by type I receptor and subsequently bind to Co-Smad, Smad4. The resulting complex translocates to the nucleus where it recruits specific co-activators, co-repressors and transcription factors to regulate the expression of target genes and microRNA that in turn will target specific mRNAs. This pathway is strictly controlled by different means. Extracellular antagonists/inhibitors (Dan, Twisted, Noggin, etc.) and decoy receptors (Bambi) and co-receptors (endoglin, beta-glycan, RGM/dragon, RTKs…) in the plasma membrane regulate binding of BMP ligand to its membrane serine/threonine kinase receptors. Additional regulators include CK2, I-Smads, phosphatases (PP1 and PP2A) and ubiquitin ligases among others. BMP also activate several non-Smad pathways, including Rho small GTPases, LIMK, PI3K/AKT, PKC and ERK, JNK and p38 MAPKs which modulate BMP cellular responses. Bambi: BMP and activin membrane bound inhibitor; CK2: Casein kinase II; ILK: Integrin-linked kinase; LIM kinase: Lin-11/Isl-1/Mec-3 gene products kinase; MAPK: mitogen-activated protein kinase; PI3K phosphatidylinositol 3-kinase; PP1: Protein phosphatase 1; PP2A: Protein phosphatase 2A; RGM: repulsive guidance molecules; RTK: receptor tyrosine kinases; TAK: TGF-β-activated kinase; TAB: TAK binding proteins.

Figure 2

Role of BMP signalling in liver regeneration (A) and liver fibrosis (B). (A) Following a partial hepatectomy (PH), BMP signalling is reduced in liver, with a decreased expression of BMP2, BMP4 and BMP9 and a decrease in phospho-Smad1,5,8 (P-Smad1,5) levels. Different approaches show that BMP7, adenovirus-mediated expression of Noggin or ALK3 (BMP receptor type 1A) deletion/inhibition have a pro-regenerative effect in liver, whereas other BMP ligands such as BMP9, increase liver damage; (B) An upregulation of different BMP ligands has been observed in response to liver insults of different nature, such as bile duct ligation, CCl₄ treatment and others. Accumulating data evidence a protective role for BMP7 in the context of liver fibrosis. Inhibition or deletion of BMP9 has a similar antifibrotic effect, while ALK3 inhibition favours liver fibrosis. The role of other BMPs is currently a matter of study. PH: partial hepatectomy; TAA: thioacetamide; DMN: dimethylnitrosamine; BDL: bile duct ligation; NAFLD: Non-Alcoholic Fatty Liver Disease; HBV: hepatitis B virus; EMT: epithelial to mesenchymal transition; HSC: hepatic stellate cells.