In Situ and In Vivo Rules of Focal Adhesion Kinase in Tendon Development and Mechanotransduction
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Focal Adhesion
Mechanotransduction
Tendon
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Abstract
Tendons enable locomotion by transmitting high tensile mechanical forces between muscle and bone via their dense extracellular matrix (ECM). The application of extrinsic mechanical stimuli via muscle contraction is necessary to regulate healthy tendon physiology. Specifically, applied physiological levels of mechanical loading elicit an anabolic tendon cell response, including tendon hypertrophy and increased ECM synthesis. Conversely, decreased mechanical loading evokes a degradative tendon state, yielding increased catabolic enzyme synthesis and ECM degradation. Interestingly, the tendon response to extrinsic mechanical loading has implications in tendon disease pathogenesis and clinical treatment strategies. Nevertheless, the cellular mechanisms by which tendon cells sense and respond to mechanical stimuli within the native tendon ECM (i.e., in situ) remain largely unknown.In this dissertation, we explored the role of cell-ECM adhesions in regulating in situ cell mechanotransduction by perturbing the genetic expression and signaling activity of focal adhesion kinase (FAK) through many experimental approaches, including tendon-derived monolayer cell culture, ex vivo tendon explants, and a novel genetic mouse model. Ultimately, we found that FAK signaling is a critical regulator of in situ tendon cell mechanotransduction. Specifically, we determined that FAK regulates tendon cell spreading behavior and focal adhesion morphology, nuclear deformation in response to applied mechanical strain, and changes in mechanosensitive gene expression in response to altered mechanical stimuli. In addition, our data revealed that FAK signaling plays an essential in vivo role in physiological tendon development and postnatal growth, as FAK-KO tendons demonstrated reduced tendon size, altered mechanical properties, differences in cellular composition, and reduced maturity of the deposited ECM. These data provide a foundational understanding of the role of FAK signaling in tendons from which future experiments may be conducted. Importantly, increased understanding of in situ tendon cell mechanotransductive mechanisms may inform clinical practice as well as lead to the discovery of diagnostic and/or therapeutic molecular targets.