Mechanics and Synergistic Signaling of Fibronectin, Integrins, and TGF-β Isoforms

Abstract

Fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis, chronic kidney disease, and cancer are marked by an excess accumulation of extracellular matrix (ECM). This process involves the assembly of the ECM protein fibronectin (FN) into insoluble fibrils. FN fibril assembly is highly linked with integrin signaling, TGF-β1 signaling, and cellular contractility. This linkage consists of four stages: (i) Integrin binding and contractile forces facilitate the assembly of FN into insoluble fibrils; (ii) assembled FN fibrils bind the large latent complex of TGF-β1; (iii) activation of TGF-β1 from the latent complex requires integrin binding and contractile forces; and (iv) active TGF-β1 increases contractility, integrin expression, and FN assembly. The significance of integrin signaling and TGF-β1 signaling in fibrotic diseases is well-appreciated, as numerous clinical trials targeting integrins or TGF-β1 have been reported. However, despite a clear effort to target integrins and TGF-β1 clinically, the vast majority of these trials have failed or have been terminated. These suggest a potentially incomplete understanding of the synergistic effects of these pathways. Here we present a review of both FN fibrillogenesis and TGF-β1 signaling, as well as current opinions of under-explored areas of crosstalk related to these pathways that may explain why these have not been successfully targeted in many disease states including fibrosis.

Keywords

Fibrosis / TGF-β / Fibronectin / Integrins mechanobiology

Author Contributions

Writing—Original Draft Preparation, M.M.S., C.A.L.; Writing—Review and Editing: M.M.S., C.A.L.; Project Administration, C.A.L.; Funding Acquisition, C.A.L.

Ethics Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Funding

This research was supported by the National Science Foundation via Award CBET-2302580 (M.M.S., C.A.L.).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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