Tendon is a dynamic tissue that connects muscle to bone and allows for force transmission during locomotion. Despite the importance of tendon in the overall function of the musculoskeletal system, relatively little is known about the cellular and molecular mechanisms that control its growth, maintenance and repair. Clinically, tendon injuries and diseases are among the most frequent and debilitating musculoskeletal conditions, resulting in billions of dollars in treatment costs and lost productivity. Tendon is primarily composed of a dense network of type I collagen fibrils that provides structural support to the tendon, binds and releases growth factors that regulate multiple cellular functions, and acts as a natural barrier to the infiltration of cells. The predominant cells in tendon are fibroblasts, and central feature to nearly all tendon disorders is abnormal fibroblast morphology and grossly disrupted appearance of the tendon extracellular matrix (ECM). Thus, understanding the interaction between tendon fibroblasts and their ECM environment will likely provide an important basis for the development of novel and effective therapies for these painful conditions. During periods of tendon growth, fibroblasts express matrix metalloproteinases (MMPs), a family of zinc-dependent enzymes that collectively degrade multiple ECM components, including type I collagen. While more than 20 MMPs have been described, previous studies in other tissues have identified the subgroup of membrane-type MMPs (MT-MMPs) as the proteinases that allow fibroblasts to migrate through their ECM. Within the MT-MMP subgroup, MT1- and MT2-MMP are the MMPs that appear most important for cellular movement, as cells that are deficient in either MT1- or MT2-MMP lose their ability to migrate. Both MT1- and MT2-MMP are expressed in tendon, but the role of these proteinases in tendon fibroblast migration is unknown, as is their overall importance in tendon growth. Using an informative tendon overload model that recapitulates the key elements of tendon growth, changes in MT1-MMP expression correlate with pivotal events in the growth response. Furthermore, MT1-MMP expression appears to be restricted to areas of newly formed tendon tissue. While MT2-MMP is also expressed in tendon, it has been less extensively studied as MT1-MMP, and both its pattern of expression and function is presently unclear. We posit that MT1-MMP, working alone or in concert with MT2- MMP, is a key regulator of tendon fibroblast function in response to mechanical loading of tendons. My central hypothesis is that MT1- and MT2-MMP are both required for tendon growth and function cooperatively to allow tendon fibroblast migration through the tendon ECM. This hypothesis will be rigorously tested in two Specific Aims using a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in a tendon overload model. Findings from this proposal will provide important insights into basic tendon fibroblast biology and potentially lead to future translational studies focused on MT-MMPs in the treatment of tendon injuries and diseases.
to public health is based upon the tremendous impact that tendon injuries and diseases have on mobility and quality of life. There is a substantial lack in our understanding of how tendons adapt to new stresses placed upon them, and how tendons recover from injuries. Increasing our understanding of fundamental adult tendon biology and translating this to patients is highly relevant to the NIH's mission to reduce the burdens of human disability.