Mechanical forces and signaling in connective tissue cells: cellular mechanisms of detection, transduction, and responses to mechanical deformation

Abstract

The environment provides mechanical input to tissues through ground reaction forces, gravity, barometric pressure, vibration, and contact with bodies. When tissues are deformed, resident cells are deformed in complex modes. Cells detect “outside-in” mechanical signals by diverse means, including stretch-activated ion channels and other ion channels as the plasma membrane is deformed, through integrin linkages from the matrix to the cytoskeleton, and through cadherins or desmosomes in cell-cell connections. Ion channels, particularly sodium, chloride, potassium, and calcium channels, play an important role in the signal transduced from the mechanical stimulus to a chemical signal. This signal often results in an increase in the concentration of intracellular calcium. This part of the signaling pathway is often blocked by removal of extracellular calcium. Once an initial step in signal transduction has occurred, activation of intracellular pathways initiates phosphorylation events and protein-protein associations including association of integrin β subunits with the cytoskeleton and associated proteins, such as FAK, paxillin, filamin, integrin-linked kinase (ILK), and talin. PLA, PLC, adenyl cyclase, guanyl cyclase, iNOS, and other enzymes are activated producing the second messengers: cAMP, cGMP, ATP, GTP, NO, PGE 2 , IP 3 , and DAG that act, not only in the target cell but also may have paracrine effects. Furthermore, specific pathways may be activated that drive mitogenesis (MEK/MAPK), a stress response (JAK/STAT and JNK), or other responses that result in specific gene expression through activation of transcription factors, cell division, and contraction. The chemical signal can be passed from cell to cell by mediator secretion or through gap junctions. A cell must be able to respond, then desensitize to a mechanical stimulus, just as a receptor may desensitize to a ligand. Therefore, “stop,” or inhibitory signals, are perhaps as important as “go,” or stimulatory signals with respect to a mechanical load response. A cell must be able to attenuate its response to load. This review discusses the recent concepts in mechanical signal detection, transduction, and response pathway in mammalian connective tissue cells.