NMR Spectral Markers of Cartilage Degeneration in Osteoarthritis

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DESCRIPTION (provided by applicant): Osteoarthritis (OA) is a major health concern with very limited treatment options. Understanding biochemical and molecular changes in OA cartilage can provide clues for new therapeutic targets. Furthermore, there is clearly a need for in vivo imaging techniques that can non-invasively and critically evaluate the therapeutic efficacy of new treatment methods. Magnetic resonance imaging (MRI) has been used to study cartilage degeneration by observing the changes in water content, relaxation and diffusion. However, these changes are indirect by-products of alterations in proteoglycan (PG)/collagen matrix in degenerative cartilage, and do not provide direct measures of biochemical changes. This is the gap our research is intended to fill. High Resolution - Magic Angle Spinning (HRMAS) spectroscopy is a unique non-destructive ex vivo technique that can provide direct measurement of biochemical changes in tissues. However, studies using HRMAS in human cartilage are very limited and no relationship between biochemical changes measured by HRMAS and cartilage degeneration has been established. Our long-term goal is to develop non-invasive imaging markers for early degeneration of cartilage. The goal of this proposal is to develop and validate ex vivo HRMAS techniques for evaluating biochemical changes in cartilage matrix associated with OA. The central hypothesis is that the non-destructive imaging capability of HRMAS will lead to identification of spectroscopic markers of early cartilage degeneration that can be related to the molecular changes in osteoarthritic cartilage matrix such as PG/collagen degradation. This research is an essential first step in the development of a novel, in vivo, non-invasive diagnostic tool that provides direct measurement of cartilage biochemistry for early OA. Specifically, we will 1) establish and optimize HRMAS acquisition protocols in human cartilage; 2) identify biochemical changes associated with cartilage degeneration using HRMAS. Cartilage samples will be harvested from OA patients who undergo total knee replacement and cadaver knees (controls). Cartilage degeneration will be evaluated using histology. HRMAS measurement between control and OA samples will be compared and HRMAS spectral markers for cartilage degeneration will be identified. HRMAS measurement will be correlated with PG and collagen assay quantitation as well as with immnohistochemical analysis on aggrecan and collagen cleavage neoepitopes. This project is novel in developing and applying ex vivo HRMAS techniques to characterize biochemical changes in human OA cartilage. The future extension of this to in vivo MR spectroscopy is what makes this study clinically significant and exciting. PUBLIC HEALTH RELEVANCE: Osteoarthritis (OA) affects more than 25 million Americans and is one of the leading causes of disability. Current treatment to OA is very limited and diagnosis of early cartilage degeneration remains a challenge. This proposal aims at developing a novel ex vivo NMR method to explore spectral markers for cartilage degeneration in OA. This research is an essential first step in the development of a novel, non-invasive, diagnostic tool that provides direct measurement of cartilage biochemistry for early OA, which will significantly improve patient management and clinical care of OA.