title: Therapeutic ultrasound bypasses canonical syndecan-4 signaling to activate rac1.
abstract: The application of pulsed, low intensity ultrasound is emerging as a potent therapy for the treatment of complex bone fractures and tissue damage. Ultrasonic stimuli accelerate fracture healing by up to 40% and enhance tendon and ligament healing by promoting cell proliferation, migration, and matrix synthesis through an unresolved mechanism. Ultrasound treatment also induces closure of nonunion fractures, at a success rate (85% of cases) similar to that of surgical intervention (68-96%) while avoiding the complications associated with surgery. The regulation of cell adhesion necessary for wound healing depends on cooperative engagement of the extracellular matrix receptors, integrin and syndecan, as exemplified by the wound healing defects observed in syndecan- and integrin-knock-out mice. This report distinguishes the influence of ultrasound on signals downstream of the prototypic fibronectin receptors, alpha(5)beta(1) integrin and syndecan-4, which cooperate to regulate Rac1 and RhoA. Ultrasonic stimulation fails to activate integrins or induce cell spreading on poor, electrostatic ligands. By contrast, ultrasound treatment overcomes the necessity of engagement or expression of syndecan-4 during the process of focal adhesion formation, which normally requires simultaneous engagement of both receptors. Ultrasound exerts an influence downstream of syndecan-4 and PKCalpha to specifically activate Rac1, itself a critical regulator of tissue repair, and to a lesser extent RhoA. The ability of ultrasound to bypass syndecan-4 signaling, which is known to facilitate efficient tissue repair, explains the reduction in healing times observed in ultrasound-treated patients. By substituting for one of the key axes of adhesion-dependent signaling, ultrasound therapy has considerable potential as a clinical technique.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, United Kingdom and Smith and Nephew, York Science Park, Heslington, York YO10 5DF, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Mahoney
authors.forename: Mark R
authors.initials: MR
authors.lastname: Morgan
authors.forename: Andrew
authors.initials: A
authors.lastname: Harrison
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Humphries
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bass
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002461:Cell Line, Transformed; D002465:Cell Movement; D049109:Cell Proliferation; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D017102:Fracture Healing; D006801:Humans; D039081:Integrin alpha5beta1 / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D014464:Ultrasonic Therapy; D014465:Ultrasonics; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
chemical_list: D039081:Integrin alpha5beta1; D009479:Neuropeptides; C484602:Rac1 protein, mouse; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D051571:Protein Kinase C-alpha; C526380:RhoA protein, mouse; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein