Mechanotransduction: Relevance to Physical Therapist Practice—Understanding Our Ability to Affect Genetic Expression Through Mechanical Forces

Mechanosensing cell membrane receptors are responsive to tissue deformation. (Top) Mechanical forces are sensed and transduced at cell-cell, cell-matrix, and cell-lumen interfaces through adhesion complexes, stretch-activated ion channels, or cell surface receptors. The letters “a” through “h” represent the various methods cells use to sense mechanical stimuli: a=stretch activated ion channels open to allow influx or efflux of ions; b=cilia or glycocalyx on the cell surface sense fluid shear or compression; c and d=cell contacts with adjacent cells or ECM allows cells to sense and respond to their local physical environment; e=extracellular proteins within the ECM exert forces on the cell; f=intracellular strain from cytoskeletal components transmits and senses forces across the cell membrane; g=cytoskeletal components adhere to the nuclear envelope to sense cell deformation and alter transcriptional events; and h=intracellular compression affects receptor binding events at the cell surface. (Bottom) Cell surface receptors known to be mechanosensitive include growth factor receptors, integrins, stretch-activated ion channels, and GPCRs. Once stimulated, receptors activate intracellular cytosolic mediators (represented in boxes) to initiate signaling cascades. These cascades may result in nuclear translocation of transcription factors (eg, NFKB), which influence genetic regulation and cell behavior. ECM=extracellular matrix; Wnt=wingless-type signaling pathway; EGF=epidermal growth factor; BMP=bone morphogenic protein; TGFβ=transforming growth factor beta; IGF=insulin growth factor; GPCR=G-protein-coupled receptor; GSK3=glycogen synthase kinase 3; FAK=focal adhesion kinase; ERK=extracellular signal regulated kinase; Akt=protein kinase B; SMAD=a family of signal transduction proteins that respond to TFGβ; Ca²⁺=calcium; RAS=a family of signal transduction, proteins originally identified and named for rat sarcoma cells; NO=nitrous oxide; PGE2=prostaglandin E2; NF-KB= nuclear factor kappa B; RUNX2=runt-related transcription factor 2; CREB=cyclic AMP response element binding protein; AP1=activator protein 1. Reprinted by permission of Macmillan Publishers Ltd, Nature Publishing Group, from: Bonnet N, Ferrari SL, Exercise and the skeleton: how it works and what it really does. IBMS Bonekey. 2010;7:7. Copyright 2010.