Osteoarthritis alone disables 10% of Americans older than 60 and is estimated to cost the US economy more than $60 billion annually. Arthritis is just one example of a constellation of collagen-related diseases that severely affect the quality of life of patients. As the principle tensile load-bearing molecule in animals, collagen is responsible for our ability to interact with the mechanical world around us. The first metazoans were a direct result of the evolution of collagen nearly 800 million years ago. Prior to this time, life was restricted to the confines of a single cell. Collagen, a triple helical molecule comprising the sequence gly-x-y (where x and y are typically proline and hydroxyproline respectively), is the material that binds animals together. Consistent with this idea is the fact that fibrillar collagens (I, II, III, V and XI) are virtually always found in tension. Even in cartilage, where the applied compressive load is carried by the fixed charges on glycosaminoglycans, the type II collagen fibrils are loaded in tension. Fibrillar collagens have the remarkable ability to self-assemble both longitudinally and radially. They also possess high mechanical strength. However, in this proposal we suggest that the most important feature of fibrillar collagens is that they comprise the basic building blocks of a """"""""smart"""""""" engineering material. Specifically, review of literature and our own preliminary data show that fibrillar collagen under a mechanical tensile load is more resistant than unloaded collagen to both high temperature denaturation and to bacterial collagenase degradation. If this is also true for matrix metalloproteinase (MMP) degradation, then collagen/MMP enzyme kinetics would be a function of strain. In short, collagen that is loaded or """"""""in use"""""""" would be less likely to degrade when exposed to MMP. Thus, matrix adaptation to applied mechanical load could proceed in the presence of both catabolic and anabolic molecules. Fibroblasts would not then be required to """"""""select"""""""" molecules for removal. The state of strain would determine the effectiveness of available enzymes. To test this hypothesis, acellular collagenous matrices with highly anisotropic organization and single molecules will be subjected to MMPs in the presence of varying mechanical loads. The pattern of fibrillar degradation in the bulk tissue and the rate of cleavage of the single molecules will be recorded. If collagen cleavage is a function of strain, then the implications for collagen genesis, homeostasis and disease are apparent. ? ? ?
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