Over the past two decades the outcome of basic and clinical studies on effects of stress deprivation have revolutionized everyday orthopaedic practice in such diverse areas as management of fractures of the spine and extremities, joint replacement, sports injuries, and hand surgery. Basic studies demonstrated gross, microscopic, biochemical and biomechanical evidence of rapid deterioration of joint surfaces and supporting connective tissues consequent to deprivation of physical input. Concurrent clinical studies demonstrated overwhelming benefits of early active or even passive motion. The resulting basic and clinical science consensus has culminated in the expansion of the concept of Wolff's Law of bone to include all fibrous and specialized connective tissues. However, there remain certain unavoidable circumstances where immobilization must be employed and where disabling joint contractures ensue. For this reason, it is important to delineate the mechanisms of the stress deprivation effects so as to guide potential preventive therapies. Considerable evidence suggests that a family of cell surface receptors for extracellular matrix components, the integrins and certain alternatively spliced forms of fibronectin, are critically important to the processes by which alterations in mechanical stress produces both structural and functional changes in connective tissues. The interaction of integrins with extracellular matrix (ECM) proteins including fibronectin is central to organization of extracellular matrix as well as transmittal of mechanical signals which modulate cellular metabolism and synthesis of matrix elements. The integrins, therefore, are the key not only to cell attachment and motility, but also to communication between the physical environment and the cell. For the latter reason, it is crucial to the further understanding of stress deprivation effects to study how integrin and fibronectin isoform display and function are altered under stress deprived conditions. In preliminary studies the investigators have shown that stress-deprived periarticular connective tissues (PCTs) undergo marked alterations in integrin expression. Utilizing techniques which include. immunochemistry, immunohistochemistry, molecular biology, matrix biochemistry, and cell biomechanics, they propose to investigate the following hypotheses: 1) Connective tissue fibroblasts alter integrin expression and cytoskeletal architecture in response to altered mechanical input; 2) The cytoskeleton-integrin matrix complex of connective tissue is a necessary element for tissue homeostasis and is perturbed by deprivation of mechanical stresses; 3) Fibronectin (Fn) synthesis which is necessary for maintenance of cytoskeleton-integrin matrix integrity is modulated by tensile stresses; and differing Fn isoforms may be produced under conditions of stress deprivation; 4) Certain perturbations of the cytoskeleton-integrin-matrix axis can counteract the damaging effects of stress deprivation; and 5) Adhesion characteristics of fibroblasts are altered under stress deprived conditions. The use of in vitro techniques will also permit mechanical strength of cell adhesion to be correlated with the observations on the above parameters, and will allow rapid screening of potential interventional options, including hyaluronan (HA) and HA-RGD peptides.
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