Osteopontin in Liver Fibrosis Mechanisms

Osteopontin is a multifunctional matricellular protein that plays a central role in the development and progression of liver fibrosis. It is secreted by hepatocytes, immune cells and activated hepatic stellate cells, where it binds to integrins and CD44 receptors to drive cell adhesion, chemotaxis and survival. Upon chronic liver injury, osteopontin contributes to the activation of quiescent stellate cells into collagen-secreting myofibroblasts, promotes immune cell recruitment and sustains a profibrotic microenvironment. It also modulates mechanotransduction pathways, notably those involving PAK kinases and YAP-1, which reinforce the fibrogenic phenotype through mechanosensitive control of gene expression and extracellular matrix deposition. Osteopontin levels in tissue and serum correlate with fibrosis stage, making it both a mechanistic effector and a candidate biomarker. Targeting osteopontin signalling or its transcriptional regulators—such as SOX9, c-Jun/AP-1 and CEBPA—offers new avenues for antifibrotic therapy and improved stratification of patients at risk of cirrhosis and its complications.

Research from Nature Portfolio

Studies have delineated key intracellular cascades by which integrin-mediated engagement of osteopontin reinforces fibrogenesis. One seminal work identified PAK kinases and the mechanosensitive transcriptional coactivator YAP-1 as core mediators of integrin β1 signalling in liver myofibroblasts, demonstrating that pharmacological inhibition of either pathway markedly attenuates collagen deposition and scar formation in vivo. Another foundational investigation revealed that SOX9 regulates the expression of a suite of extracellular matrix proteins, including osteopontin, and that loss of SOX9 in myofibroblasts reduces scar matrix accumulation and improves liver function in fibrotic models. These insights underscore osteopontin’s integration into mechanotransduction networks and transcriptional programmes that drive matrix remodelling.

Osteopontin in Liver Fibrosis Mechanisms publication trend

The graph below shows the total number of articles in osteopontin in liver fibrosis mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Osteopontin: Phosphorylated matricellular glycoprotein that mediates cell–matrix interactions and cytokine signalling.

Hepatic stellate cells: Perisinusoidal liver cells that transdifferentiate into fibrogenic myofibroblasts upon activation.

Myofibroblast: Contractile cell derived from stellate or mesenchymal origins responsible for extracellular matrix synthesis during scar formation.

Extracellular matrix (ECM): Complex network of collagens, glycoproteins and proteoglycans providing structural and signalling support in tissues.

Mechanotransduction: Cellular process that converts mechanical stimuli from the microenvironment into biochemical signals.

References

1. Hepatocyte-specific CCAAT/enhancer binding protein α restricts liver fibrosis progression. Journal of Clinical Investigation (2024).
2. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nature Communications (2016).
3. SOX9 predicts progression toward cirrhosis in patients while its loss protects against liver fibrosis. EMBO Molecular Medicine (2017).
4. The transcription factor c-Jun/AP-1 promotes liver fibrosis during non-alcoholic steatohepatitis by regulating Osteopontin expression. Cell Death & Differentiation (2019).
5. The Osteopontin Level in Liver, Adipose Tissue and Serum Is Correlated with Fibrosis in Patients with Alcoholic Liver Disease. PLOS ONE (2012).
6. Impact of osteopontin on the development of non‐alcoholic liver disease and related hepatocellular carcinoma. Liver International (2020).