Bone Morphogenetic Protein Signaling in Liver Fibrosis and Regeneration

Bone Morphogenetic Proteins (BMPs) are a subfamily of the Transforming Growth Factor-β superfamily that orchestrate developmental morphogenesis and adult tissue homeostasis. In the liver, distinct BMP ligands and their receptors regulate the balance between fibrogenesis and regenerative repair. BMPs signal through type I and type II serine/threonine kinase receptors, activating receptor-regulated Smad1/5/8 proteins which form complexes with Smad4 to modulate gene transcription. In chronic injury, activated hepatic stellate cells (HSCs) produce extracellular matrix (ECM) components, driving fibrosis; certain BMPs restrain this activation, whereas others exacerbate matrix deposition. Concurrently, BMPs influence hepatocyte proliferation and differentiation during regeneration. The net outcome of BMP signalling depends on ligand identity, receptor expression, co-receptors or antagonists (for example Gremlin-1 or BAMBI), and cross-talk with TGF-β pathways. Emerging data highlight circulating BMP isoforms as biomarkers for disease staging, and manipulation of BMP signalling holds promise for antifibrotic and pro-regenerative therapies in liver disease.

Research from Nature Portfolio

Recent studies have revealed that imbalanced BMP4 and its antagonist Gremlin-1 govern cellular senescence in human non-alcoholic fatty liver disease and steatohepatitis. In patient biopsies, high Gremlin-1 expression in hepatic and visceral adipose tissue correlated with senescence markers and disease severity. In three-dimensional spheroid models of human hepatocytes and HSCs, BMP4 suppressed senescence, lipid accumulation, inflammation and fibrotic gene expression, while Gremlin-1 antagonised these protective effects. Both modulators converged on the YAP/TAZ pathway, identifying it as a central regulator of hepatic cell fate. These findings position BMP4-Gremlin-1 axis modulation as a potential strategy to reverse senescence-driven progression of chronic liver injury.

Bone Morphogenetic Protein Signaling in Liver Fibrosis and Regeneration publication trend

The graph below shows the total number of articles in bone morphogenetic protein signaling in liver fibrosis and regeneration across all publications each year (not limited to Nature Index journals).

Technical terms

Bone Morphogenetic Proteins (BMPs): A group of growth factors in the TGF-β superfamily that signal via serine/threonine kinase receptors to regulate development, tissue repair and fibrosis.

Hepatic stellate cells (HSCs): Pericyte-like cells in the liver that, upon activation, transdifferentiate into myofibroblasts and secrete extracellular matrix proteins during fibrogenesis.

Extracellular matrix (ECM): A complex network of proteins and glycoproteins deposited by stromal cells that provides structural support and signalling cues to surrounding cells.

Cellular senescence: A state of permanent cell cycle arrest coupled with a pro-inflammatory secretory phenotype, implicated in tissue dysfunction and fibrosis.

Pseudoreceptor (BAMBI): A membrane-bound protein resembling TGF-β receptors but lacking kinase activity, which inhibits TGF-β/BMP signalling by competitive ligand binding.

Smad proteins: Intracellular mediators of TGF-β superfamily signalling; receptor-regulated Smad1/5/8 propagate BMP signals to the nucleus when complexed with Smad4.

References

1. BMP Signalling at the Crossroad of Liver Fibrosis and Regeneration. International Journal of Molecular Sciences (2017).
2. Expression and Function of BMP and Activin Membrane-Bound Inhibitor (BAMBI) in Chronic Liver Diseases and Hepatocellular Carcinoma. International Journal of Molecular Sciences (2023).
3. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nature Metabolism (2022).
4. Circulating bone morphogenetic protein 8A is a novel biomarker to predict advanced liver fibrosis. Biomarker Research (2023).
5. Circulating Bone morphogenetic protein 9 (BMP9) as a new biomarker for noninvasive stratification of nonalcoholic fatty liver disease and metabolic syndrome. Clinical and Experimental Medicine (2024).
6. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut (2017).