Project 3: Intraarticular Mineralization

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ABSTRACT Project 3: Intra-Articular Mineralization Intra-articular (IA) mineralization due to calcium crystal deposition is common in knee osteoarthritis (OA), and may contribute to inflammation, structural pathology, and pain. However, prior studies have been conflicting regarding its clinical relevance, likely partly due to reliance on relatively insensitive radiographs. In addition, the particular crystal type may have different consequences in OA. We plan to address these key knowledge gaps by use of dual energy CT (DECT) to more sensitively detect IA mineralization, and apply a novel image analysis method to differentiate type of crystal present in the IA mineralization. We hypothesize that IA calcium crystal deposition may induce low-grade inflammation that can contribute to pain and its fluctuation in OA. Further, particular types of calcium crystal (calcium pyrophosphate [CPP] vs. basic calcium phosphate [BCP]) may contribute differently to OA outcomes. Clarification of potential consequences of IA mineralization and specific crystal types in knee OA would enable examination of IA mineralization as a treatment target in OA with therapies such as anti-IL-1β or other anti-cytokine therapy addressing inflammation due to crystals. We will leverage data collected in the Multicenter Osteoarthritis (MOST) Study, including previously acquired DECT and stored blood biospecimens, and take advantage of the planned synovial fluid acquisition in conjunction with the proposed MOST4 Project 4 on synovial fluid proteomics. Using these rich data, we propose to evaluate the following: 1) the relation of IA mineralization to pain fluctuation over two years; 2) the relation of IA mineralization to serum inflammatory markers; 3) type of crystal (CPP vs. BCP) and volume of each type using novel DECT image analysis, and determine the extent to which each crystal type is related to serum inflammatory signatures, structural progression, and pain; 4) To examine the synovial inflammatory signatures via proteomics in knees with crystal-proven CPP vs. BCP (exploratory pilot aim). We will work with Dr. Fabio Becce who has developed the novel image analysis methods to differentiate crystal type on DECT, as well as with Dr. Ann Rosenthal who will use Fourier transform infrared spectroscopy to identify crystal type in synovial fluid to permit proteomics analysis of synovial fluid containing CPP vs. BCP. In exploratory analysis using deep learning, we will evaluate the relationship of crystal type to co-localized predicted cartilage loss. These proposed studies are innovative as they will provide novel insights into the inter-relationships between IA crystals, inflammation, pain, and pathology in OA. The proposed research is significant as such insights would lay the foundation for identifying an important OA phenotype targetable by effective anti-cytokine therapy leading to disease modification. This would provide an important breakthrough for this disease in which there are no disease-modifying therapies available to date.