Regulated Assembly of the Tendon Extracellular Matrix

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DESCRIPTION (provided by applicant): Tendons connect muscle to bone and have a primary function in transmitting and withstanding tensile loads. Tendons are prone to injury because they are subjected to large and/or repetitive loads. These injuries cause significant pain as well as disability and are common in sports, work environments and aging. The regulatory mechanisms involved in tendon-specific extracellular matrix assembly and development of a functional tendon are the focus of the current application. The data obtained will provide important parameters for understanding normal tendon development, growth, maturation as well as changes associated with aging, injury and repair. Our general hypothesis is that tendon matrix assembly is a multi-step process, with each step requiring specific regulatory interactions. Our previous work has identified 3 key steps in tendon matrix assembly; nucleation of fibril assembly; deposition and stabilization of immature fibril intermediates as well as their entrance into the growth phase; and linear and lateral fibril growth, generating the mature fibrils required for tendon function. We hypothesize that the regulation of these steps involve: heterotypic type V/XI collagen interactions with type I collagen; changing interactions with FACIT collagen types XII and XIV; and interactions with small leucine-rich proteoglycans (SLRPs) involving 2 SLRP classes, decorin and biglycan; and lumican and fibromodulin. The specific aims are to: (1) determine the role(s) of heterotypic interactions involving collagens type I and type V/XI in nucleation of tendon fibril assembly; (2) identify the functional roles of (FACIT) collagen types XII and XIV in stabilization of fibril intermediates during deposition into fibers and entrance into fibril growth; and (3) determine the functional roles of fibril interactions with SLRPs in the regulation of fibril growth steps. Mouse models null for typeV/XI isoform expression, FACIT collagen types XII and XIV and SLRPs will be utilized. Mice with single or compound deficiencies will be analyzed during development using ultrastructural and morphometric approaches. These approaches will be integrated with biochemical, immunochemical and molecular analyses to define specific functional interactions. Definition of the regulatory steps in tendon-specific matrix assembly provides a foundation to further our understanding of tendon repair/regeneration, pathological changes and the modulation of these processes.