Project 3: Intraarticular Mineralization

摘要项目3：关节内矿化 由于钙结晶沉积导致的关节内矿化在膝关节骨关节炎(OA)中很常见。 可能导致炎症、结构性病理和疼痛。然而，之前的研究一直相互矛盾。 关于其临床相关性，部分原因可能是依赖相对不敏感的X光照片。此外， 在骨性关节炎中，特定的晶体类型可能会有不同的后果。我们计划解决这些关键的知识差距 使用双能量CT(DECT)更灵敏地检测IA矿化，并应用一种新的图像分析 区分IA矿化中晶体类型的方法。我们假设IA钙晶体 沉积可能导致低级别炎症，从而导致骨性关节炎的疼痛及其波动。此外， 特定类型的钙晶体(焦磷酸钙[CPP]与碱性磷酸钙[BCP])可能 对开放存取成果的贡献有所不同。澄清IA矿化的潜在后果和特定的 膝骨性关节炎的晶体类型将使IA矿化的检查成为治疗膝骨性关节炎的治疗靶点 如抗IL-1、β或其他抗细胞因子疗法，解决因晶体引起的炎症。我们将利用数据 收集在多中心骨关节炎(MOST)研究中，包括以前获得的DECT和储存的血液 生物检疫，并利用计划中的滑液采集与拟议的 滑液蛋白质组学MOST4项目4。利用这些丰富的数据，我们建议评估以下内容：1) IA矿化与两年来疼痛波动的关系2)IA矿化与血清的关系 炎症标志物；3)晶体类型(CPP与BCP)和每种类型的体积使用新的DECT图像 分析并确定每种晶体类型与血清炎症征象相关的程度， 结构进展和疼痛；4)通过蛋白质组学检查膝关节滑膜炎症征象 以水晶验证的CPP与BCP(探索性试点目标)进行比较。我们将与Fabio BECCE博士合作，他已经开发出 DECT上区分晶体类型的新图像分析方法以及与Ann Rosenthal博士的合作 将使用傅里叶变换红外光谱来鉴定滑液中的晶体类型，以实现蛋白质组学 含CPP和BCP的滑液分析。在使用深度学习的探索性分析中，我们将评估 晶体类型与共局性预测软骨丢失的关系。这些拟议的研究具有创新性，因为 他们将对IA晶体、炎症、疼痛和病理之间的相互关系提供新的见解 在办公自动化中。拟议的研究具有重要意义，因为这样的见解将为确定一个重要的 以有效的抗细胞因子治疗为靶点的骨性关节炎表型可导致疾病的改变。这将提供 对这种疾病的一个重要突破是到目前为止还没有可以改变疾病的治疗方法。

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.