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Mechanical forces direct cellular activities to induce tissue adaptation. Extrinsically and intrinsically generated mechanical forces load musculoskeletal tissues, with the characteristics of the resultant tissue forces being dependent on the ability of the tissue to resist those forces. Tissue forces are transmitted to the micromechanical environment of resident cells, with cellular mechanical properties influencing the characteristics of the cellular forces. Cells can modify their micromechanical environment via cytoskeletal rearrangement, which feeds back to alter cellular sensitivity to incoming forces. When cellular forces are sufficient, the cell initiates a molecular response, which ultimately alters synthesis or degradation of the extracellular matrix. The latter alters tissue mechanical properties, which feeds back to influence tissue forces.
Common micromechanical stimuli to which musculoskeletal cells are exposed: (A) tension—pulling force that increases cell dimensions in the direction of pull; (B) compression—pushing force that decreases cell dimensions in the direction of push; (C) shear—parallel forces pushing or pulling in opposite directions to distort the cell; (D) hydrostatic pressure—pressure exerted by surrounding fluid that changes cell volume; (E) vibration—oscillating, reciprocal back-and-forth shaking of a cell; and (F) fluid shear—force created by the flow of fluid parallel to a cell membrane.
Transducing mechanical signals into biochemical responses requires unique machinery. Forces are transmitted at the matrix/cell membrane interface where specialized complexes called focal adhesions form. Integrins span the plasma membrane, uniting the extracellular matrix with the internal actin cytoskeleton. Linker proteins, such as vinculin and talin, reinforce the structural integrity of the adhesion complex, and associated signaling effectors, including focal adhesion kinase (FAK) and Src, activate biochemical signaling pathways in response to force.
A variety of extracellular receptors activate an overlapping network of mechanosensitive pathways. (A) Musculoskeletal cells can sense incoming mechanical signals using a diverse group of transmembrane mechanosensitive proteins (mechanosensors), including stretch-activated ion channels, cell-membrane spanning G-protein-coupled receptors, growth-factor receptors, and integrins. The mechanical stimulation of these proteins can lead to changes in their affinity to binding partners or ion conductivity. (B) Mechanical stimulation of the mechanosensors and alteration in their binding capacity or ion conductivity converts the mechanical signal into a biochemical signal (biochemical coupling) triggering intracellular signaling cascades. Many of the pathways overlap sharing signaling molecules. The convergence of the pathways results in the activation of select transcription factors, including nuclear factor of activated T cells (NFAT), nuclear factor-κβ (NF-κβ), activator protein 1 (AP1), GATA4 (a member of the transcription factor family characterized by the ability to bind the DNA sequence “GATA”), and signal transducer and activator of transcription factors (STATs). The transcription factors translocate to the nucleus and modulate the expression of a panel of mechanosensitive genes, including early growth response 1 (Egr1), lex1, Fos, Jun, and cyclo-oxygenase-2 (Cox2). Ultimately, the net sum of gene-expression reprogramming determines the functional response of the cell to a mechanical stimulus. Akt/PKB=protein kinase B; CaMK=calcium/calmodulin-dependent kinase; DAG=diacyl-glycerol; ERK=extracellular signal-regulated kinase; FAK=focal adhesion kinase; IP3=inositol triphosphate; JNKs=c-Jun N-terminal kinases; MEK=mitogen-activated protein kinase; MEKK=mitogen-activated protein kinase; MLCK=myosin light-chain kinase; NO=nitric oxide; NOS=nitric oxide synthase; PAK=p21-activated kinase; PI3K=phosphoinositide 3-kinase; PKC=protein kinase C; PLC=phospholipase C; Raf=rapidly accelerated fibrosarcoma kinase; Ras=rat sarcoma small GTPase.
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