Therapeutic Ultrasound Bypasses Canonical Syndecan-4 Signaling to Activate Rac1

• Published in: The Journal of biological chemistry Vol. 284; no. 13; pp. 8898 - 8909
• Main Authors: Mahoney, Claire M., Morgan, Mark R., Harrison, Andrew, Humphries, Martin J., Bass, Mark D.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2009; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Adhesion; Cell Line, Transformed; Cell Movement; Cell Proliferation; Enzyme Activation; Extracellular Matrix - genetics; Extracellular Matrix - metabolism; Focal Adhesions - genetics; Focal Adhesions - metabolism; Fracture Healing; Humans; Integrin alpha5beta1 - genetics; Integrin alpha5beta1 - metabolism; K562 Cells; Mechanisms of Signal Transduction; Mice; Mice, Knockout; Neuropeptides - genetics; Neuropeptides - metabolism; Protein Kinase C-alpha - genetics; Protein Kinase C-alpha - metabolism; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - metabolism; rac1 GTP-Binding Protein; rho GTP-Binding Proteins - genetics; rho GTP-Binding Proteins - metabolism; rhoA GTP-Binding Protein; Signal Transduction; Syndecan-4 - genetics; Syndecan-4 - metabolism; Ultrasonic Therapy; Ultrasonics
• ISSN: 0021-9258; 1067-8816; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M804281200

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, α5β1 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 PKCα 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.