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Pathway Description
Mechanisms of Fibrosis
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Signaling
Created: 2025-03-13
Last Updated: 2025-05-15
Fibrosis is a pathological condition marked by the excessive deposition of extracellular matrix (ECM) components, leading to the thickening and scarring of tissues. This process is often triggered by chronic injury, inflammation, or dysregulated wound healing, where normal tissue repair mechanisms become dysregulated, resulting in pathological tissue remodeling. A central pathway driving fibrosis is the TGF-β signaling pathway. When TGF-β binds to its receptors (TGF-β receptor type-1/2), it activates SMAD 2/3, which then forms the SMAD 2-3-4 complex. This complex translocates into the nucleus, where it activates genes that promote the production of ECM proteins like collagen and fibronectin, contributing to the progressive deposition of these components and the formation of scar tissue. This ECM accumulation is a hallmark of fibrosis. Additionally, SMAD7 and ERK 1/2 act as negative regulators, providing feedback to prevent excessive fibrosis. Another key player in fibrosis is the Wnt/β-catenin pathway, which plays a crucial role in the activation of fibroblasts and their transformation into myofibroblasts, the primary cells responsible for the excessive production of ECM. In this pathway, the binding of Wnt-1 to the Frizzled receptor complex results in the stabilization of β-catenin, which then translocates to the nucleus and activates transcription factors that promote fibroblast proliferation and differentiation. Myofibroblasts are characterized by their contractile properties and their ability to secrete large amounts of ECM, including collagen, driving tissue stiffness and fibrosis.
Additionally, the Rho GTPase signaling pathway is crucial for the cytoskeletal dynamics and contractility of fibroblasts. Rho-GTP, once activated, stimulates Rho-associated protein kinase 1 (ROCK1), which influences the formation of actin filaments and promotes the contractile behavior of myofibroblasts. This contractility is important in fibrosis because it helps pull the ECM components together, leading to tissue stiffening and scarring. Furthermore, Integrin α-1/β-1, activated by interactions with collagen chains such as collagen alpha-1(I) and collagen alpha-2(I), facilitates the formation of focal adhesion complexes, which link the ECM to the actin cytoskeleton, enabling fibroblasts to migrate and exert force during tissue remodeling. These integrin-ECM interactions, combined with the activation of transcription factors such as YAP1 and TAZ, further enhance the fibrotic response by promoting gene expression associated with ECM production and myofibroblast differentiation.
References
Mechanisms of Fibrosis References
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