Mechanotransduction and fibrosis

Abstract

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

Keywords: Fibrosis; Mechanical signaling; Mechanotransduction; Scarring.

Fig. 1

Extracellular Mechanotransduction. The ECM is a dynamic structure possessing multiple functions and is directly regulated by mechanical force. Mechanical forces can expose hidden domains and alter spatial density of growth factors within the ECM, thereby influencing cell behavior. Finally, cytokines such as TGF-β can bind to ECM domains and be released based on mechanical cues (Wong et al., 2011). Reprint with permission.

Fig. 2

Intracellular Mechanotransduction. The most important mediators of transduction signals from the biomechanical environment include integrin-matrix interactions, growth factor receptors (e.g., for TGF-β), G protein-coupled receptors (GPCRs), mechanoresponsive ion channels (e.g., Ca²⁺), and cytoskeletal strain responses. Once transmitted over the cell membrane, mechanical force activates multiple interrelated signaling pathways including calcium-dependent targets, nitric oxide signaling, mitogen-associated protein kinases (MAPKs), RhoGTPases, and phosphoinositol-3-kinase (PI3K) (Wong et al., 2011). Reprint with permission.

Fig. 3

The Hippo Pathway in Mechanotransduction. The highly conserved mammalian Hippo pathway, with its two main downstream effectors YAP and TAZ, represents an important connection between biomechanical cues, the cytoskeleton and cell behavior. Among its transcriptional targets are connective tissue growth factor (CTGF) and TGF-β, both of which playing important roles in the development of fibrosis, as well as transglutaminase-2, a molecule involved in ECM deposition, turnover and crosslinking. This makes YAP and TAZ potentially attractive therapeutic targets.