TGF-β LAP Degradation Products, a Novel Biomarker and Promising Therapeutic Target for Liver Fibrogenesis

Abstract

While there are many blood and/or tissue biomarkers as well as algorithms clinically used to assess hepatic fibrosis, a good biomarker and therapeutic target of hepatic fibrogenesis, which reflects prefibrotic changes, has not been established. The most fibrogenic cytokine, transforming growth factor (TGF)-β, is produced as a latent complex, in which TGF-β is trapped by its propeptide. On the surface of activated hepatic stellate cells, plasma kallikrein activates TGF-β by cleaving latency-associated protein (LAP) between the R58 and L59 residues, releasing active TGF-β from the complex. We made specific antibodies that recognize neo-C-terminal (R58) and N-terminal (L59) ends of LAP degradation products (LAP-DPs) and found that LAP-DPs may serve as a novel surrogate marker of TGF-β activation—namely, generation of active TGF-β—and is thus a therapeutic marker for TGF-β-mediated liver fibrogenesis in patients and can also be used to monitor effects of anti-fibrogenic factors or compounds for discovery of a novel anti-fibrosis drug.