Type XI collagen is an integral component of the collagen fibrils of cartilage, along with types II and IX collagen. This heterotypic fibrillar assembly functions with the proteoglycan component of cartilage to provide the necessary biomechanical properties required during development, growth and in the adult as articular cartilage. It is the goal of this application to determine the mechanism by which type XI collagen plays a role in extracellular matrix assembly and maintenance of integrity of cartilage as a tissue. Previous work has documented that the alpha chain of type XI collagen is essential for skeletal differentiation and development. In addition, mutations in both the alpha1 and apha2 chains have been linked to early onset osteoarthritis, hearing loss and alterations in the vitreous humor that can lead to retinal detachment in Stickler and Marshall syndromes. Our laboratory has described the alternative splicing of the mRNA that encodes the amino terminal domain of alpha1 (XI) collagen chain which results in striking structural diversity expressed specifically with respect to developmental stage and tissue type. To date, the effect of regulated fibril growth attributed to type XI collagen has been explain by steric hindrance by the amino pro-peptides on the surface of collagen fibrils. The actual mechanism is likely to be more complex. This grant proposal is designed to test the hypothesis that isoforms of alpha1 (XI) collagen of the extracellular matrix that mediate extracellular matrix assembly and tissue integrity. Regulated proteolytic removal of this domain is also an important mechanistic detail that will be investigated The alpha1 (XI) chain may have an additional function in that the expression of a specific isoform may indicate the fate of cartilage (i.e. permanent cartilage or to become bone) in both normal development and disease. Understanding the details of the mechanism of type XI collage function has broad relevance to regulated extracellular matrix assembly and organization. Results of these studies will provide new information about normal skeletal development and the assembly of the extracellular matrix. In addition, this new information could facilitate the rational design of therapeutic agents with the potential to modulate excessive collagen deposition and poor organization of collagen fibrils characteristic of fibrosis, a problem in major organs such as the heart, kidney, liver, long, eye, blood vessels and skin. The ability to modulate the assembly of the extracellular matrix could be of great significance in the field of tissue engineering as well.
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